WO2006013851A1 - Dispositif a utiliser dans une cavite du corps et preparation a liberation continue - Google Patents

Dispositif a utiliser dans une cavite du corps et preparation a liberation continue Download PDF

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Publication number
WO2006013851A1
WO2006013851A1 PCT/JP2005/014107 JP2005014107W WO2006013851A1 WO 2006013851 A1 WO2006013851 A1 WO 2006013851A1 JP 2005014107 W JP2005014107 W JP 2005014107W WO 2006013851 A1 WO2006013851 A1 WO 2006013851A1
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WIPO (PCT)
Prior art keywords
present
vivo
sustained
carrier
pharmaceutically active
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PCT/JP2005/014107
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English (en)
Japanese (ja)
Inventor
Noritada Asai
Junzo Seki
Akira Saheki
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Nippon Shinyaku Co., Ltd.
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Publication of WO2006013851A1 publication Critical patent/WO2006013851A1/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
    • A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M31/00—Devices for introducing or retaining media, e.g. remedies, in cavities of the body
    • A61M31/002—Devices for releasing a drug at a continuous and controlled rate for a prolonged period of time
    • A—HUMAN NECESSITIES
    • 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
    • A61K47/30—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
    • A—HUMAN NECESSITIES
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • 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
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels

Definitions

  • the present invention mainly relates to a device for intracorporeal body and a sustained-release preparation for intracorporeal body such as a device cover.
  • Non-Patent Documents 1 and 2 various anti-tumor agents for bladder cancer (for example, see Non-Patent Documents 1 and 2), urinary urinary incontinence treatments such as oxiputinin (for example, Non-Patent Document 3), Administration of therapeutic agents for urinary tract infections such as antibiotics and therapeutic agents for interstitial cystitis such as dimethyl sulfoxide (DMSO) to the urinary bladder has been performed.
  • DMSO dimethyl sulfoxide
  • the treatment method in which a liquid agent is injected into the bladder using a catheter for intravesical instillation that is currently being performed is a patient's urination for 12 hours in order to keep the drug in the bladder.
  • Patients have to administer fluids frequently in the bladder because it is difficult to keep the drug in the bladder for a long time.
  • Thomas B. Ottoboni et al. Have developed a sustained-release formulation for intravesical infusion using a device that is biodegrading or bioeroding! /, E.g. (see Patent Document 2, for example).
  • the device using a biodegradable or biodegradable material gradually weakens over time or gradually erodes from the surface and becomes smaller. Therefore, when it becomes weak gradually, the shape of the device cannot be maintained by the bladder contraction pressure during urination, and it becomes very difficult to control the holding time of the device in the bladder.
  • the surface force gradually erodes and becomes smaller, there is a high risk of inducing urethral obstruction when the size of the device is slightly larger than or comparable to that of the urethral section! ).
  • Patent Document 1 International Publication No. 99Z24106 Pamphlet
  • Patent Document 2 Special Table 2001—519787
  • Non-Patent Document 1 Bulletin of Urology, 36 ⁇ , 257-263, 1999
  • Non-patent document 2 Jichi-Drug Journal, 39 ⁇ , No. 12, 1531-1533, 2003
  • Non-patent document 3 Medical pharmacy, 30 ⁇ , No.2, 83-87, 2004
  • Non-Patent Document 4 Journal of the Japan Urological Association, 76 ⁇ , No.2, 197-203, 1985
  • An object of the present invention is to provide a device for body cavity or body that is mainly retained in a body hole for a certain period of time, releases a sufficient pharmaceutically active ingredient in the body hole, and can be discharged spontaneously without causing occlusion. It is to provide a long-lasting preparation for pores.
  • the present inventors have found a device for body hole that can achieve the above object, and have completed the present invention.
  • an intracorporeal device hereinafter referred to as “the device of the present invention” which is an assembly of in vivo corrosion-resistant carrier pieces integrated with an in-vivo erodible substance. (See Figure 2).
  • the present invention includes, for example, a continuous preparation for intracorporeal cavity in which a pharmaceutically active ingredient is retained in the device of the present invention (hereinafter “the preparation of the present invention”).
  • Examples of the “body cavity” according to the present invention include bladder, uterus, vagina and stomach.
  • the “in-body device” refers to a device that is inserted into a body hole and used.
  • the “in-vivo corrosion-resistant carrier” according to the present invention is a living body at least within a desired period. A carrier that is not decomposed, absorbed, dissolved or weakened in the body.
  • the “in vivo erodible substance” refers to a substance that is decomposed, dissolved or weakened in vivo after a desired period of time.
  • FIG. 1 shows a schematic diagram of the behavior of a conventional intravesical device for intravesical injection over time.
  • the circle portion indicates the bladder
  • the portion on the tube protruding from the circular portion force indicates the urethra
  • the white portion indicates the intravesical injection device.
  • FIG. 2 shows a schematic view of the behavior of the device of the present invention or the preparation of the present invention over time in the bladder.
  • the circular portion indicates the bladder
  • the portion on the tube protruding the circular partial force indicates the urethra
  • the white circular shape indicates a small piece of carrier
  • the filamentous shape indicates an erodible substance in vivo.
  • FIG. 3 shows the swelling behavior of a dry in-vivo corrosion-resistant carrier.
  • the vertical axis represents the gel weight (g) of the carrier, and the horizontal axis represents the retention time (hour) in which the gel is immersed in physiological saline.
  • FIG. 4 shows a schematic view of a shape change of the raft-like assembly according to the present invention over time of the device of the present invention or the preparation of the present invention.
  • the white bar indicates a carrier piece, and the thread indicates a bioerodible substance.
  • FIG. 5 shows a schematic view of a shape change of the pseudo-spherical aggregate according to the present invention over time of the device of the present invention or the preparation of the present invention.
  • the white rod-shaped object indicates a small piece of carrier and is a thread-shaped object Indicates an erodible substance in the living body.
  • FIG. 6 shows a schematic view of a change in shape of the beaded aggregate according to the present invention over time of the device of the present invention or the preparation of the present invention.
  • a white circle indicates a carrier piece, and a broken line portion indicates a filamentous in vivo erodible substance.
  • FIG. 7 shows a schematic diagram of a change in shape of the sea water-like aggregate according to the present invention over time of the device of the present invention or the agent of the present invention.
  • the hollow bar-like shape indicates a carrier piece, and the broken line portion indicates a filamentous in vivo erodible substance.
  • FIG. 8 shows a schematic diagram of the shape change of the net-like aggregate according to the present invention over time of the device of the present invention or the preparation of the present invention.
  • the white spheres represent carrier pieces, and the net-like pieces represent in vivo erodible materials knitted to wrap around each carrier piece.
  • Fig. 9 is a schematic view showing a shape change of a device of the present invention or a preparation of the present invention over time in an assembly in which carrier pieces according to the present invention are bonded with an adhesive.
  • the white rectangles indicate carrier pieces, and the black parts indicate the bioerodible material that adheres each carrier piece.
  • FIG. 10 shows the change over time in the amount of doxorubicin hydrochloride released according to the formulation of the present invention.
  • the vertical axis represents the residual ratio of doxorubicin hydrochloride in the preparation of the present invention according to Example 8 (
  • FIG. 11 shows the change over time in the amount of doxorubicin hydrochloride released according to the preparation of the present invention according to Example 9.
  • the vertical axis represents the doxorubicin hydrochloride residual rate (%) in the preparation of the present invention according to Example 9, and the horizontal axis represents the release time (day).
  • the device of the present invention is an assembly of in vivo corrosion resistant carrier pieces integrated with an in vivo erodible substance.
  • Examples of the method for integrally bonding include a method of suturing, bonding, or enveloping the carrier piece with a body eroding substance.
  • the device of the present invention or the preparation of the present invention can be inserted into a body hole, for example.
  • the carrier piece swells or the overall shape of the device of the present invention is maintained in the body hole. It changes to a size or shape that can be held and is held in the body hole for a certain period of time.
  • the device of the present invention is not discharged while being held in the body hole. For example, even when the device of the present invention is inserted into the bladder, normal urination is possible.
  • the assembly according to the present invention After the assembly according to the present invention is held in the body hole for a certain period of time, the erodible substance in the living body is decomposed, dissolved, or weakened, so that the assembly is separated into carrier pieces at a stretch and spontaneously discharged.
  • the device of the present invention when the device of the present invention is inserted into the bladder, it is discharged as a carrier piece together with urine during urination.
  • the in vivo corrosion-resistant carrier according to the present invention includes, for example, polybulal alcohol (PVA), polymethyl methacrylate (PMMA), polyethylene vinyl acetate copolymer (EVA), poly (2-hydroxyethyl methacrylate) ) (PHEMA), Darcomannan, calcium alginate, silicone, polyurethane, polyethylene terephthalate, polyethylene, polypropylene and V, one or more of the following polymers.
  • PVA polybulal alcohol
  • PMMA polymethyl methacrylate
  • EVA polyethylene vinyl acetate copolymer
  • PHEMA poly (2-hydroxyethyl methacrylate)
  • Darcomannan calcium alginate, silicone, polyurethane, polyethylene terephthalate, polyethylene, polypropylene and V, one or more of the following polymers.
  • the carrier may be electrically neutral, or may be partially or totally charged.
  • the method for producing the carrier is, for example, as follows.
  • a carrier made of PVA for example, PVA is dissolved in water, and the aqueous solution is placed in a suitable cage or the like, and then freezing and thawing at room temperature are repeated several times (freeze-thawing method).
  • the gel can be produced by bringing it into contact with an aqueous solution containing a crosslinking agent to cause a crosslinking reaction. If necessary, the gel may be dried.
  • strong cross-linking agents include aldehyde compounds such as formaldehyde and acetoaldehyde, N-methylol compounds such as methylol urea and dimethylol urea, dicarboxylic acid compounds such as terephthalic acid, or 1, 2, 3, 4 Examples thereof include bisepoxide compounds such as epoxybutane and 1,2,7,8-diepoxyoctane.
  • the cross-linking agent is formaldehyde
  • the temperature of the aqueous formaldehyde solution is suitably 5 to 40 ° C and more preferably 10 to 40 ° C. It is.
  • the reaction time varies depending on the reaction temperature and the like. Usually, 10 minutes to 5 hours is appropriate.
  • the formal degree of PVA for example, rather than preferably 10 to 50 mol%, preferably from 20 to 40 Monore 0/0 force! / ⁇ .
  • PVA is dissolved in water, and the aqueous solution is made into a suitable bowl shape or the like. It can be manufactured by applying radiation (eg, ⁇ -rays) to gelled material. The irradiation time is usually 10 minutes to 5 hours. You can also dry the gel if necessary!
  • radiation eg, ⁇ -rays
  • a support made of soot or EVA for example, PMMA or EVA and a divinyl compound such as dibutene benzene are dissolved in an appropriate solvent, and an appropriate amount of a reaction initiator is added as necessary, and the reaction is performed in a nitrogen atmosphere.
  • the gel produced by stirring in can be produced by placing in a suitable mold. If necessary, the gel may be dried.
  • the reaction initiator include benzoyl peroxide, lauroyl peroxide, tamenhydride peroxide, di-tert-butyl peroxide, bis-tert-butylcyclohexyloxydicarbonate, diisopropylperoxydicarbonate.
  • Organic peroxides such as soot can be mentioned.
  • the addition amount of the reaction initiator is suitably 0.01 to 4% by weight, for example.
  • reaction solvent examples include hydrocarbons such as pentane, hexane, heptane, cyclohexane, benzene, and tolylene, and these can be used alone or as a mixed solvent of two or more.
  • the polymerization temperature is, for example, suitably from 78 ° C to 200 ° C, preferably from 0 ° C to 160 ° C, more preferably from 30 ° C to 160 ° C.
  • the reaction time varies depending on the type of raw material used, reaction temperature, etc. Usually, 1 to 48 hours is appropriate.
  • a carrier composed of PHEMA for example, it can be produced by placing an aqueous solution of 2-hydroxyethyl methacrylate monomer by heat polymerization and gelling it into a suitable mold or the like. If necessary, the gel may be dried.
  • the reaction temperature is, for example, 25-: LOO ° C.
  • the reaction time varies depending on the reaction temperature and the like. Usually, 1 to 24 hours is appropriate.
  • a carrier that also has darcomannan power for example, after dissolving darcomannan in water without stirring and stirring, an appropriate amount of alkali such as calcium hydroxide is stirred and gelled. It can be manufactured by placing the product in a suitable saddle mold or the like. If necessary, the gel may be dried. The amount of alkali added is, for example, 0.05 to 3% by weight.
  • an aqueous solution of sodium alginate is dissolved in water while stirring under heat and cooled, and then brought into contact with a calcium chloride aqueous solution and gelled, and then molded into a suitable mold or the like. Can be manufactured. If necessary, the gel may be dried.
  • An appropriate concentration of the calcium chloride aqueous solution is, for example, 0.1 to 5% by weight.
  • a carrier made of silicon, polyurethane, polyethylene terephthalate, polyethylene, or polypropylene it can be produced by cutting each polymer by a conventional method.
  • examples of the in vivo corrosion-resistant carrier according to the present invention include a carrier having two kinds of strength, PVA and sodium alginate (see Example 1).
  • Such a carrier is, for example, a solution in which PVA and sodium alginate are dissolved in water while stirring, and the mixed aqueous solution is gelled by repeatedly freezing and thawing at room temperature several times. (Freeze-thaw method). If necessary, the gel may be dried.
  • the mixing ratio of PVA and sodium alginate is, for example, 20 to 160 parts by weight of sodium alginate is suitable with respect to 100 parts by weight of PV A, 60 to 140 parts by weight of sodium alginate is preferable, and 80 to 120 parts by weight of sodium alginate is more preferable. Sodium alginate is more preferred.
  • the method of drying the gel is, for example, a force that can be allowed to stand at room temperature, or drying by reducing the pressure. It can also be accelerated. These methods can also be used in combination.
  • the in-vivo corrosion-resistant carrier piece according to the present invention can be obtained by using an arbitrary saddle type in the process of producing an in-vivo corrosion-resistant carrier, or by using an in-vivo corrosion-resistant carrier in a conventional manner. It can be manufactured by further cutting.
  • Examples of the shape of the carrier piece according to the present invention include a spherical shape, a rod shape, and a rectangular parallelepiped.
  • a spherical in-vivo corrosion-resistant carrier piece can be produced by using a spherical saddle.
  • the in-vivo corrosion-resistant carrier produced by using a rod-like or sheet-like saddle type can be cut with scissors or the like to produce, for example, a rod-like or rectangular parallelepiped in-vivo corrosion-resistant carrier piece. .
  • the size of the carrier piece before insertion is, for example, a rod shape
  • Diameter 0.05 ⁇ : LOmm, Length l ⁇ 150mm is suitable, Diameter 0.1 ⁇ 7mm, Length 2 ⁇ 1 OOmm force is preferable, Diameter 0.5 ⁇ 5mm, Length 10 ⁇ : LOOmm More preferred.
  • a diameter of 0.05-: LOmm is appropriate, a diameter of 0.1-7 mm is preferred, and a diameter of 0.5-5 mm is more preferred.
  • the diameter after swelling should be 10 mm or less in order to pass through the urethra. It is preferably 7 mm or less, and more preferably 5 mm or less.
  • the size of the carrier piece before insertion is, for example, a spherical shape, for example, a diameter of 0.05 to 10 mm is appropriate, and a diameter of 0.1 to 7 mm is preferable. A diameter of 0.5 to 5 mm is more preferable.
  • the diameter after swelling is preferably 10 mm or less, and 7 mm or less. It is more preferable that it is 5 mm or less.
  • the size of the carrier piece before insertion is, in the case of a rod, for example, a diameter of 0.05-: LOmm, a length of l-150 mm is suitable, and a diameter of 0.1 l A diameter of 0.5 to 5 mm and a length of 10 to 100 mm are more preferable.
  • a diameter of 0.05-: LOmm is appropriate, a diameter of 0.1-7 mm is preferable, and a diameter of 0.5-5 mm is more preferable.
  • the size of the carrier piece before insertion is, for example, a rod shape, for example, a diameter of 0.05 to 20 mm, a length of 1 to: LOOmm, and a diameter of 0.1 l ⁇ 15 mm and length of 2 to 70 mm are more preferable. Diameter of 0.5 to: LOmm and length of 5 to 50 mm are more preferable. In the case of a spherical shape, for example, a diameter of 0.05 to 20 mm is appropriate, and a diameter of 0.1 to 15 mm is preferable. Further, a diameter of 0.5 to: LOmm is more preferable.
  • the carrier piece is Force Since it is necessary to be discharged into the small intestine, even if it swells in the stomach, for example, the diameter after swelling should be 20 mm or less, preferably 15 mm or less, and more preferably 10 mm or less. It is more preferable.
  • the bioerodible substance according to the present invention is indispensable for holding the device of the present invention in a body hole for a certain period of time and for forming an aggregate.
  • Examples of the bioerodible substance according to the present invention include substances that are gradually decomposed, dissolved, or weakened. However, after the elapse of a certain period of time, when the erodible substance in the living body does not have sufficient strength to maintain the aggregate, separation into aggregate force carrier pieces must occur at once.
  • Examples of in vivo erodible substances according to the present invention include polyglycolic acid (PGA), polylactic acid (PLA), poly force prolataton (PCL), polydioxanone (PDS), and copolymers thereof. Mention may be made of filaments, nets and pastes composed of one or more of collagen, gelatin, hyaluronic acid, fibrin, chitin and chitosan.
  • the method for producing the in vivo erodible substance is, for example, as follows.
  • the filamentous bioerodible substance can be produced by a general spinning method, for example, a dry spinning method, a wet spinning method, a dry wet spinning method, or a melt spinning method.
  • a net-like product can be produced by weaving a thread-like in-vivo erodible substance.
  • the paste-like bioerodible substance can be produced by dispersing or dissolving the raw material polymer in an appropriate solvent.
  • the solvent used include halogen-based hydrocarbons such as dichloromethane and chloroform, alcohols such as methanol and ethanol, hydrocarbons such as hexane and heptane, and water.
  • an absorbable suture (OPEPOLIX (registered trademark) S, AZUEL Co., Ltd., material: PGA) used for surgery can be mentioned.
  • Absorbable sutures are useful because they are excellent in safety, easy to control the degradation period, and excellent in workability.
  • the retention time of the device of the present invention in the bladder can be easily controlled.
  • a suitable retention period is, for example, a range of 1 day to 3 months, and a range of 1 day to 1 month is preferred.
  • a raft-like assembly (see Fig. 4) or a pseudo-spherical assembly (see Fig. 4) produced by stitching a carrier piece with a thread-like bioerodible substance. 5), bead-like aggregates (see Fig. 6), sea anemone-like aggregates (see Fig. 7), and nets produced by enveloping the carrier pieces in a net-eroded material.
  • An assembly (see FIG. 8) and a rod-like assembly (see FIG. 9) produced by bonding a carrier piece with a paste-like bioerodible substance can be given.
  • the size of the device of the present invention before being inserted into the body hole is that the aggregate of the above shape is folded, rolled, compressed, or physically deformed by drying or dried, and dried from the urethra. Size that can be inserted into the bladder, from the vaginal opening through the outer uterine ostium, into the uterus, or into the mouth or nasal force, into the stomach, to be inserted into the vagina, or to be swallowable The size is appropriate.
  • Examples of the instrument for inserting the device of the present invention into the bladder from the urethral cage include, for example, a bladder injection catheter, a bladder endoscope, and a metal catheter-like insertion instrument (for example, Non-Patent Document 4).
  • Examples of the bladder injection catheter include those having a diameter of 8 to 26 Fr (2.7 to 8.7 mm) and a length of 150 to 420 mm.
  • An example of an instrument for inserting the device of the present invention from the vaginal opening through the external uterine ostium into the uterus is a catheter.
  • Examples of the catheter include those having a diameter of 8 to 26 Fr (2.7 to 8.7 mm) and a length of 150 to 420 mm.
  • examples of instruments for inserting the device of the present invention into the stomach with mouth and nasal force include a gastric tube catheter.
  • the catheter include those having a diameter of 10 to 18 Fr (3.3 to 6. Omm) and a length of 900 to 1250 mm.
  • the size of the device of the present invention after being inserted into a body hole changes, for example, in the bladder, uterus, vagina,
  • the size is not particularly limited as long as it is a size that is retained in the stomach and is, for example, less than the capacity of the bladder, eclampsia, vagina, and stomach.
  • a pharmaceutically active ingredient is retained in the device of the present invention. That is, the present invention
  • the preparation retains the pharmaceutically active ingredient in the in vivo erodible substance or the in vivo corrosion resistant carrier piece constituting the device of the present invention.
  • the inclusion form of the pharmaceutically active ingredient held in the device of the present invention is not particularly limited. For example, it may be uniformly dissolved or dispersed in the device of the present invention, or may be concentrated locally.
  • the pharmaceutically active ingredient and the device of the present invention may be included, adsorbed, complexed, or chelated by electrostatic, hydrophobic, or ionic interaction.
  • the powerful pharmaceutically active ingredient is released by the diffusion of the in-vivo corrosion-resistant carrier fragment force or by the disintegration or dissolution of the in-vivo erodible substance.
  • the preparation of the present invention is held in the body pore, the whole amount of the pharmaceutically active ingredient held in the device of the present invention may be released or only a part thereof may be released. That is, the release control of the pharmaceutically active ingredient of the preparation of the present invention can control both the release control of the pharmaceutically active ingredient held in the device of the present invention and the discharge control of the carrier pieces forming the aggregate according to the present invention. it can. Therefore, the controlled release of the pharmaceutically active ingredient of the preparation of the present invention can be controlled by appropriately adjusting the combination, mixing ratio, etc. of the applied pharmaceutically active ingredient and in vivo erodible substance or in vivo anticorrosive carrier piece. It can be carried out.
  • this invention formulation can contain an oil component or an emulsifier.
  • the release of the pharmaceutically active ingredient can also be controlled by including an oil component or an emulsifying agent.
  • the pharmaceutically active ingredient is encapsulated in an ribosome mainly composed of an emulsifier or an emulsion mainly composed of an oil component and an emulsifier. Or the thing currently hold
  • Such a form can also control the release of the pharmaceutically active ingredient.
  • the inclusion form of the emulsion or ribosome held in the device of the present invention is not particularly limited.
  • the emulsion or ribosome may be uniformly dispersed in the device of the present invention or may be concentrated locally. Further, emulsions and ribosomes may interact to form an aggregate. In addition, an electrostatic, hydrophobic, or ionic interaction occurs between the emulsion or ribosome and the device of the present invention (in vivo erodible substance or in vivo anticorrosive carrier piece)! / Yo! /
  • the content of the pharmaceutically active ingredient varies depending on the place where the pharmaceutically active ingredient is retained in the preparation of the present invention, the desired release time of the pharmaceutically active ingredient, the type of the pharmaceutically active ingredient, the oil ingredient, the emulsifier, and other other ingredients. For example, 0.01 to 50% by weight of the pharmaceutically active ingredient is suitable for the preparation of the present invention, and 0.1 to 20% by weight is preferred.
  • the oil component is not particularly limited as long as it is an oil component that can be used for a pharmaceutical preparation, and examples thereof include vegetable oils, animal oils, neutral lipids, synthetic lipids, and sterol derivatives.
  • vegetable oils include soybean oil, cottonseed oil, rapeseed oil, sesame oil, corn oil, peanut oil, and safflower oil.
  • animal oils include fish oil.
  • neutral lipids include monodaliselide, diglyceride, and triglyceride, and more specific examples include triolein, trilinolein, tripalmitin, tristearin, trimyristin, and triarachidonin.
  • synthetic lipids include azone.
  • sterol derivative examples include cholesteryl oleate, cholesteryl linoleate, cholesteryl myristate, cholesteryl palmitate, and cholesteryl arachidate. These can be used alone or in combination of two or more.
  • Preferable oil components include vegetable oils such as soybean oil mainly composed of triglycerides.
  • the content of the oil component varies depending on the location and type of the oil component to be used, the type of the pharmaceutically active ingredient to be retained, the desired release time of the pharmaceutically active ingredient, other contained components, and the like. On the other hand, the range of 0.1 to 30% by weight is suitable, and the range of 1 to 20% by weight is preferable.
  • the emulsifier is not particularly limited as long as it is an emulsifier that can be used for pharmaceutical preparations, and examples thereof include pharmaceutically acceptable phospholipids and pharmaceutically acceptable nonionic surfactants.
  • phospholipid for example, phosphatidylcholine (soy phosphatidylcholine, egg yolk phosphatidylcholine, distearoyl phosphatidylcholine, dipalmitoylphosphatidylcholine, etc.), phosphatidylethanolamine (distearoylphosphatidylethanolamine, etc.), phosphatidylserine, Examples include phosphatidic acid, phosphatidylglycerol, phosphatidylinositol, lysophosphatidylcholine, sphingomyelin, and lecithin.
  • nonionic surfactant examples include polyalkylene glycol (for example, polyethylene glycol having an average molecular weight of 1,000 to 10,000, preferably 4000 to 6,000), and a polyoxyalkylene copolymer (for example, an average molecular weight of 1,000 to 20,000, preferably 6000-10000 polyoxyethylene polyoxypropylene copolymers), hydrogenated castor oil polyoxyalkylene derivatives (eg, hydrogenated castor oil polyoxyxylene (20) -ether, hydrogenated castor oil polyoxyxylene (40) Ether, hydrogenated castor oil polyoxylylene- (100) -ether, etc.), castor oil polyoxyalkylene derivatives (eg, castor oil polyoxyxylene (20) ether, castor oil polyoxyxylene (40) ether, castor oil And polyoxylylene mono (100) -ether etc.).
  • Preferred examples of the emulsifier include egg yolk phosphatid
  • the content of the emulsifier varies depending on the location and type of the emulsifier to be used, the type of pharmaceutically active ingredient to be retained, the desired release time of the pharmaceutically active ingredient, other contained components, etc. In the range of 0.05 to 40% by weight, the range of 0.1 to 20% by weight is preferable.
  • the pharmaceutically active ingredient is held in the device of the present invention (at least one of an in vivo erodible substance and an in vivo corrosion resistant carrier piece) in a form encapsulated in a microcapsule.
  • a form can also control the release of the pharmaceutically active ingredient.
  • the inclusion form of the microcapsules encapsulating the pharmaceutically active ingredient held in the device of the present invention is not particularly limited.
  • the microcapsules may be uniformly dispersed or locally concentrated in the device of the present invention. Good.
  • microcapsules encapsulating a pharmaceutically active ingredient may interact to form an aggregate.
  • an electrostatic, hydrophobic, or ionic interaction may occur between the microcapsule and the device of the present invention (in vivo erodible substance or in vivo anticorrosive carrier piece).
  • microcapsules for controlled release of a pharmaceutically active ingredient, in particular limited, such ⁇ mosquito s, I Retsue if ,, Journal of controlled release, 70 Certificates, 1- 20, 2001, a microphone port capsules Kyoritsu Shuppan Tamotsu Kondo al 1985 can be referred to.
  • a microphone port capsules Kyoritsu Shuppan Tamotsu Kondo al 1985 can be referred to.
  • the microcapsules include polylactic acid (PLA), polyglycolic acid (PGA), polystrength prolatatone (PCL), polydioxanone (PDS), and copolymers thereof, ethyl cellulose, gelatin, chitosan, and sodium alginate. Or what consists of 2 or more types can be mentioned.
  • microcapsule examples include a microcapsule of a copolymer of PLA and PGA used in Leuplin (registered trademark) of Takeda Pharmaceutical Co., Ltd. (for example, a pharmaceutical magazine, 111 ⁇ ). , No. 8, 397-409, 1991).
  • the content of the microcapsule varies depending on the location and type of the microcapsule used, the type of pharmaceutically active ingredient to be retained, the desired release time of the pharmaceutically active ingredient, other contained ingredients, etc.
  • the present invention The range of 0.05 to 40% by weight is appropriate for the preparation, and the range of 0.1 to 20% by weight is preferred.
  • the pharmaceutically active ingredient that can be used in the present invention is not particularly limited. Specific examples include the following pharmaceutically active ingredients.
  • BCG BCG, doxorubicin hydrochloride, cytarabine, thiotepa, mitomycin C, pirarubicin hydrochloride, epilubicin hydrochloride, pepromycin and cisplatin.
  • Pentamidine isethionate, cefmenoxime, kanamycin, fradiomycin, erythromycin, josamycin, tetracycline, minocycline, chloramphenicol, streptomycin, midecamycin, amphotericin B, itraconazole, nystatin and polymyxin sulfate.
  • the dosage of the preparation of the present invention can be appropriately set according to the dosage of the pharmaceutically active ingredient to be applied, or the treatment of symptoms and the protocol required for the patient.
  • Examples of the method of adjusting the dosage of the preparation of the present invention include, for example, a method of adjusting the length or size of the in vivo corrosion-resistant carrier piece, the number of the carrier piece and the length of the in vivo erodible substance, or A method for adjusting the thickness can be mentioned.
  • ingredients such as pharmaceutically active ingredients, other oil ingredients and emulsifiers should be added at an appropriate stage in the process of producing the in vivo corrosive resistant carrier or in vivo corrosive substance constituting the device of the present invention. Can do. Then, the carrier piece according to the present invention can be produced by appropriately cutting the in-vivo corrosion-resistant carrier holding the pharmaceutically active ingredient. For example, in the case of producing an in-vivo corrosion-resistant carrier in which a pharmaceutically active ingredient is retained using a freeze-thaw method, when the polymer is dissolved in water, the pharmaceutically active ingredient, the pharmaceutically active ingredient and the oil ingredient, the emulsifier It is appropriate to add components such as.
  • the preparation of the present invention is a biocorrosion-resistant carrier using at least one of the in-vivo corrosion-resistant carrier piece and the bioerodible substance in which the pharmaceutically active ingredient thus produced is retained. It can be manufactured by forming a collection of small pieces.
  • Example 1 Production of In vivo Corrosion Resistant Carrier or Carrier Piece 5 g of polyvinyl alcohol (trade name: Gohsenol (registered trademark) NH-20, Nippon Synthetic Chemical Co., Ltd.) and 5 g of sodium alginate (Nacalai Testa Co., Ltd.) were dissolved in 90 mL of water without stirring. This mixed aqueous solution was stored at ⁇ 20 ° C. for 2 hours or more and completely frozen. After that, it was thawed at room temperature and gelled by repeating freeze-thawing a total of 4 times to obtain an in-vivo corrosion-resistant carrier.
  • polyvinyl alcohol trade name: Gohsenol (registered trademark) NH-20, Nippon Synthetic Chemical Co., Ltd.
  • sodium alginate Nacalai Testa Co., Ltd.
  • thermo-hygrostat LH-21-13M type, Nagano Science Co., Ltd.
  • a low humidity condition 25 ° C and 40% RH, and a 37 ° C physiological saline solution. When soaked, it rapidly re-swelled about 10 times (weight) in 1 hour (see Fig. 3).
  • Example 1 By the method shown in Example 1, a small gel-like carrier piece having a diameter of 4 mm and a length of 40 mm was produced. Four of these carrier pieces are connected to a surgical absorbable suture (trade name: OPEPOLIX (registered trademark) S, thread number 5-0, AZUEL, material: PGA) in a raft shape and dried. An inventive device was manufactured (see the leftmost figure in FIG. 4). This could be filled into an intravesical catheter with an inner diameter of 3 mm. When this device of the present invention was stored in physiological saline at 37 ° C., it re-swelled to almost the state before drying, the absorbent sewing thread was broken and the carrier pieces were separated in about 1.5 months.
  • OPEPOLIX registered trademark
  • thread number 5-0 thread number 5-0
  • AZUEL AZUEL
  • material: PGA material
  • Example 1 By the method shown in Example 1, a small gel-like carrier piece having a diameter of 4 mm and a length of 40 mm was produced. After drying these four carrier pieces, surgical absorbent absorbable sutures (trade name: Opepolix (registered trademark) S, thread number 5-0, AZuel, material: PGA)
  • the device of the present invention was manufactured in a raft shape (see the leftmost figure in Fig. 5). This could be filled into an intravesical catheter with an inner diameter of 3 mm by rolling.
  • the device of the present invention was stored in physiological saline at 37 ° C, it re-swelled to almost the state before drying, and further, the carrier small piece swelled and shifted up and down to become a pseudo-sphere (Fig. 5). (See the middle figure.)
  • the absorbable suture was cut in about 1.5 months and became loose.
  • a small spherical gel-like carrier piece having a diameter of 4 mm was produced by the method shown in Example 1.
  • This carrier At the center of each of the 40 small pieces, the surgical absorbable suture (trade name: Opepolix (registered trademark) S, thread number 5-0, AZuel, material: PGA) is gathered and dried,
  • the device of the present invention was manufactured by tying both ends of the suture into a rosary shape (see the left end view of FIG. 6). This was folded in half and filled into an intravesical catheter with an inner diameter of 3 mm.
  • this device of the present invention was stored in physiological saline at 37 ° C., it re-swelled to almost the state before drying, and in about 1.5 months, the absorbent suture was broken and the carrier pieces were separated.
  • a fine gel-like carrier piece having a diameter of 3 mm and a length of 15 mm was produced by the method shown in Example 1. Pass through 12 pieces of this carrier through a surgical absorbable suture (trade name: OPEPOLIX (registered trademark) S, thread number 5-0, AZUEL Co., Ltd., material: PGA), and dry the two ends of the suture.
  • the device of the present invention was manufactured (see the leftmost diagram in FIG. 7). This could be filled into an intravesical catheter with an inner diameter of 3 mm by rolling.
  • This device according to the present invention is stored in a physiological saline solution at 37 ° C, and re-swells to a state almost before drying. Further, the device tied in a thread is squeezed and both ends are formed into an anemone-like shape. (See Figure 7). When stored in physiological saline at 37 ° C, the absorbable suture broke and fell apart in about 1.5 months.
  • a small spherical gel-like carrier piece having a diameter of 2 mm was produced by the method shown in Example 1.
  • the carrier piece is dried, and a surgical absorbable suture (trade name: OPEPOLIX (registered trademark) S, thread number 5-0, AZuel, material: PGA) is put into a net-knitted bag and the present invention.
  • the device was manufactured (see the leftmost figure in Fig. 8). When this device of the present invention was stored in physiological saline at 37 ° C, it re-swelled to almost the state before drying, the absorbent suture was broken in about 1.5 months, and the carrier pieces were separated.
  • Example 1 By the method shown in Example 1, a small gel-like carrier piece having a diameter of 4 mm and a length of 40 mm was produced.
  • Absorbable surgical sutures (trade name: OPEPOLIX (registered trademark) S, thread number 5-0, Azu Co., Ltd.), which were dried after four pieces of the carrier were stored in distilled water at 50 ° C for 5 days.
  • the device of the present invention When the device of the present invention was stored in physiological saline at 37 ° C, it re-swelled to almost the state before drying, and further, the carrier piece swelled and shifted up and down to become a pseudosphere (see Fig. 5). (See the middle figure). When stored in physiological saline at 37 ° C as it was, the absorbable suture was broken and disintegrated in about 2 weeks.
  • Example 8 Method for Forming the Formulation of the Present Invention Containing Doxorubicin Hydrochloride: Pseudospherical Assembly 1 Polyvinyl Alcohol (Product Name: Gohsenol (Registered Trademark) NH-20, Nippon Synthetic Chemical Co., Ltd.) 0.5 g in water 8. Added to 9 mL and dissolved with warming and stirring. Thereafter, 0.1 g of doxorubicin hydrochloride (Wako Pure Chemical Industries, Ltd.) and 0.5 g of sodium alginate (Nacalai Testa Co., Ltd.) were added and dissolved by stirring.
  • doxorubicin hydrochloride Wako Pure Chemical Industries, Ltd.
  • sodium alginate Nacalai Testa Co., Ltd.
  • This mixed aqueous solution was filled into a silicon tube having an inner diameter of 7 mm, stored at ⁇ 20 ° C. for 2 hours or more, and completely frozen. Thereafter, this was thawed at room temperature, gelled by repeating freeze-thawing a total of 4 times, and then cut to produce a carrier piece having a diameter of 7 mm and a length of 60 mm. After drying 4 pieces of this carrier, absorbable surgical sutures (trade name: OPEPOLIX (registered trademark) S, thread number 5-0, AZuel, material: PGA). The preparation of the present invention containing a doxorubicin hydrochloride in a V-shaped shape was produced (see the leftmost diagram in FIG. 5).
  • Example 9 Method for Forming Formulation of the Present Invention Containing Doxorubicin Hydrochloride: Pseudospherical Assembly 2 Polyvinyl Alcohol (Product Name: Gohsenol (Registered Trademark) NH-20, Nippon Synthetic Chemical Co., Ltd.) 0.5 g in water 8. Added to 9 mL and dissolved with warming and stirring. Thereafter, 0.1 g of doxorubicin hydrochloride (Wako Pure Chemical Industries, Ltd.) and 0.5 g of sodium alginate (Nacalai Testa Co., Ltd.) were added and dissolved by stirring.
  • doxorubicin hydrochloride Wako Pure Chemical Industries, Ltd.
  • sodium alginate Nacalai Testa Co., Ltd.
  • This mixed aqueous solution was filled into a silicon tube having an inner diameter of 4 mm, stored at ⁇ 20 ° C. for 2 hours or more, and completely frozen. Thereafter, this was thawed at room temperature, gelled by repeating freeze-thaw a total of 4 times, and then cut to produce a carrier piece having a diameter of 4 mm and a length of 40 mm. After drying 4 pieces of this carrier, absorbable surgical sutures (trade name: OPEPOLIX (registered trademark) S, thread number 5-0, AZuel, material: PGA). The preparation of the present invention containing a doxorubicin hydrochloride in a V-shaped shape was produced (see the leftmost diagram in FIG. 5).
  • Test Example 1 Dog Test 1 The device of the present invention according to Example 3 was transurethrally inserted into a beagle dog (2 females).
  • the tip of a catheter (Nelton Catheter, Terumo Co., Ltd.) is filled with the device of the present invention, the catheter is inserted transurethrally, and a tube made of Teflon (registered trademark) is inserted into the catheter. Extrusion was performed.
  • the device of the present invention was retained in the bladder for 21 days and 22 days after insertion, and then excreted with urine in a state where the carrier pieces were separated. During this time, Inu showed no abnormalities in renal function values (urine nitrogen, creatinine, uric acid) from blood tests that did not cause urethral obstruction.
  • the device of the present invention according to Example 5 was transurethrally inserted into a beagle dog (2 females).
  • the tip of a catheter (Nelton Catheter, Terumo Co., Ltd.) is filled with the device of the present invention, the catheter is inserted transurethrally, and a tube made of Teflon (registered trademark) is inserted into the catheter. Extrusion was performed.
  • the device of the present invention was retained in the bladder for 26 days after insertion, and then discharged together with urine in a state where the carrier pieces were separated. During this time, Inu also showed no abnormalities in renal function values (urea nitrogen, creatine, uric acid) from blood tests that did not cause urethral obstruction.
  • the device of the present invention according to Example 5 was transurethrally inserted into a beagle dog (two males).
  • the tip of a catheter (Nelton Catheter, Terumo Co., Ltd.) is filled with the device of the present invention, the catheter is inserted transurethrally, and a tube made of Teflon (registered trademark) is inserted into the catheter. Extrusion was performed.
  • the device of the present invention was retained in the bladder for 24 days after insertion, and then excreted with urine in a state where the carrier pieces were separated. During this time, Inu also showed no abnormalities in renal function values (urea nitrogen, creatine, uric acid) from blood tests that did not cause urethral obstruction.
  • the device of the present invention according to Example 7 was transurethrally inserted into a beagle dog (1 female).
  • the tip of a catheter (Nelton Catheter, Terumo Co., Ltd.) is filled with the device of the present invention, the catheter is inserted transurethrally, and a tube made of Teflon (registered trademark) is inserted into the catheter. Extrusion was performed.
  • the device of the present invention is the bladder for 9 days after insertion. After being held inside, the carrier pieces were discharged together with urine in a state of falling apart. During this time, Inu showed no abnormalities in renal function values (urea nitrogen, creatine, uric acid) from blood tests that did not cause urethral obstruction.
  • Test Example 5 Drug release test of the formulation power of the present invention containing doxorubicin hydrochloride in the in vitro mouth 1
  • An in vitro drug release test of the preparation of the present invention according to Example 8 was performed using a dissolution tester TD S-30P (Toyama Sangyo Co., Ltd.). As the release solution, 500 mL of Ringer's solution was used. The absorbance (476 nm) of the released solution was measured using a UV-visible spectrophotometer (UV-1600 type, Shimadzu Corporation), and the residual ratio (%) of doxorubicin hydrochloride contained in the preparation of the present invention was determined. The discharge solution was changed once a day.
  • Test Example 6 Drug release test of the formulation power of the present invention containing doxorubicin hydrochloride in the in vitro mouth 2
  • An in vitro drug release test of the preparation of the present invention according to Example 9 was performed using a dissolution tester TD S-30P (Toyama Sangyo Co., Ltd.).
  • As the release solution 500 mL of Ringer's solution was used.
  • the absorbance (476 nm) of the released solution was measured using an ultraviolet-visible spectrophotometer UV-1600 type (Shimadzu Corporation), and the residual ratio (%) of doxorubicin hydrochloride contained in the preparation of the present invention was determined.
  • the discharge solution was changed once a day.
  • the device of the present invention is an assembly obtained by suturing, adhering or wrapping an in-vivo corrosion-resistant carrier piece with an in-vivo erodible substance. Changes in shape can be retained in the body pores for a certain period of time, release the active pharmaceutical ingredient in the body pores, and the bioerodible substance will be decomposed, absorbed, dissolved or weakened after a certain period of time. As a result, the aggregate is separated into carrier pieces and discharged naturally without causing clogging. That is, the device of the present invention can allow a pharmacologically effective concentration of a pharmaceutically active ingredient to stay in the body pore for a long period of time, and the carrier small piece is spontaneously discharged from the body pore after a certain period of time. The inside of a body hole can be returned to a clean state, and it is useful as a preparation for local diseases for body holes (eg, bladder, uterus, vagina, stomach).
  • body holes eg, bladder, uterus, vagina, stomach.

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Abstract

L'invention est relative à un dispositif destiné à être utilisé dans une cavité du corps, qui peut séjourner dans la cavité du corps pendant une durée définie tout en libérant en quantité suffisante une substance pharmaceutique active, pour être ensuite éliminé sans provoquer d'obstruction. Elle porte également sur une préparation à libération continue à utiliser dans une cavité du corps. Le dispositif précité, qui se compose d'une masse de petites pièces d'un support biologiquement non corrosif combinées au moyen d’une substance biologiquement non invasive, peut être inséré dans une cavité du corps. Dans la cavité du corps, les petites pièces du support gonflent ou le dispositif tout entier change de forme ou de taille, de manière à pouvoir séjourner dans la cavité du corps. Après avoir séjourné dans la cavité du corps pendant une durée définie, la substance biologiquement non invasive est décomposée, dissoute ou affaiblie et dès lors la masse se désintègre immédiatement en ses éléments, permettant l'élimination spontanée des petites pièces.
PCT/JP2005/014107 2004-08-03 2005-08-02 Dispositif a utiliser dans une cavite du corps et preparation a liberation continue WO2006013851A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2013523745A (ja) * 2010-03-28 2013-06-17 エベストラ・インコーポレイテッド 膣内薬物送達デバイス
JP2022531163A (ja) * 2019-04-30 2022-07-06 トリゴン ファーマ リミテッド 膀胱への薬剤滴下投与用の製剤および方法と、膀胱疾患の治療

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH02185264A (ja) * 1988-12-16 1990-07-19 Ferring Bv 膀胱内又は尿管へ薬を送り込む方法及び装置
JP2001519787A (ja) * 1997-04-03 2001-10-23 ポイント バイオメディカル コーポレイション 膀胱内ドラッグデリバリーシステム
JP2001522665A (ja) * 1997-11-06 2001-11-20 サイタス コーポレイション 膀胱内注入装置

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH02185264A (ja) * 1988-12-16 1990-07-19 Ferring Bv 膀胱内又は尿管へ薬を送り込む方法及び装置
JP2001519787A (ja) * 1997-04-03 2001-10-23 ポイント バイオメディカル コーポレイション 膀胱内ドラッグデリバリーシステム
JP2001522665A (ja) * 1997-11-06 2001-11-20 サイタス コーポレイション 膀胱内注入装置

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2013523745A (ja) * 2010-03-28 2013-06-17 エベストラ・インコーポレイテッド 膣内薬物送達デバイス
JP2022531163A (ja) * 2019-04-30 2022-07-06 トリゴン ファーマ リミテッド 膀胱への薬剤滴下投与用の製剤および方法と、膀胱疾患の治療
JP7350372B2 (ja) 2019-04-30 2023-09-26 トリゴン ファーマ リミテッド 膀胱への薬剤滴下投与用の製剤および方法と、膀胱疾患の治療

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