WO2015133580A1 - Injectable poly(lactic acid)-containing composition - Google Patents

Injectable poly(lactic acid)-containing composition Download PDF

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WO2015133580A1
WO2015133580A1 PCT/JP2015/056535 JP2015056535W WO2015133580A1 WO 2015133580 A1 WO2015133580 A1 WO 2015133580A1 JP 2015056535 W JP2015056535 W JP 2015056535W WO 2015133580 A1 WO2015133580 A1 WO 2015133580A1
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composition
present invention
lactic acid
solvent
drug
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PCT/JP2015/056535
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French (fr)
Japanese (ja)
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鈴木 秀一
有史 高島
悠祐 長谷川
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わかもと製薬株式会社
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/185Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic, hydroximic acids
    • A61K31/19Carboxylic acids, e.g. valproic acid
    • A61K31/195Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/196Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K31/41Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/41641,3-Diazoles
    • A61K31/41841,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47Quinolines; Isoquinolines
    • A61K31/4709Non-condensed quinolines and containing further heterocyclic rings
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K31/53Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/56Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives, e.g. steroids
    • A61K31/57Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane, progesterone
    • A61K31/573Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane, progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/56Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives, e.g. steroids
    • A61K31/58Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/0019Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/0043Nose
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/0046Ear
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/0048Eye, e.g. artificial tears
    • A61K9/0051Ocular inserts, ocular implants
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/0085Brain, e.g. brain implants; Spinal cord
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers

Abstract

 This composition contains at least one type of poly(lactic acid) and at least one type of solubulizing solvent for the same, and is an aqueous solution in which poly(lactic acid) is dissolved by a solubilizing solvent. This composition can be administered as an ordinary injection due to being pharmacologically acceptable. Compounding a drug with this composition makes it possible to provide a pharmaceutical that can be expected to have a long-term therapeutic effect even without frequent administration because the drug can be released over an extended period of time at the administration site. This composition also makes it possible to provide a pharmaceutical that need not be removed after treatment because the pharmaceutical is highly safe and finally disappears completely within the body. This composition can also be manufactured simply without using substances harmful to the human body, and can be applied to many drugs.

Description

Injectable poly lactic acids containing compositions

The present invention can be administered as a general injection relates to compositions that can be expected long-term therapeutic effect without frequent administration to release the drug over a prolonged period of time at the site of administration.

Many therapeutic agents are rapidly metabolized in the body after administration to disappear, to maintain adequate therapeutic concentrations must be administered drug frequently.
As described in Patent Document 1, in order to avoid this frequent administration, techniques using implants having controlled release capabilities of the drug is well known.
Some controlled release implants are type "matrix". That is, the drug is not dispersed in a matrix comprising a porous or non-porous type of polymer, the matrix is ​​a solid or semi-solid, and a permeable or impermeable to the active ingredient.
Matrix implant, for example, if they are formed from a biodegradable material such as poly lactic acids is advantageous in that drugs with decomposition of the implant is released, in order to further implant itself is gradually degraded loss, drug It has the advantage that it is not necessary to remove even after release.
The biodegradable implant is superior in sustained release of the drug, and has an excellent advantage that it is not necessary to finally remove the device. However, the administration of a biodegradable implants must be embedded incised site of administration, inevitable invasion upon administration of patient. Therefore, also implants biodegradable, has the disadvantage that can not be used in difficult affected area to incision.

In the field of medicine, and treatment of safety, the minimally invasive treatment of thinking that does not put a burden on the patient it is adapted to be emphasized. Along with this, technology and to design and synthesize a safer material, techniques of administering into the body is required.
To solve this problem, Patent Document 2, the implant is molded as fine particles, depot preparation administered by using a needle without incising the affected area have been proposed. In this way, there is no need to finally take out the implant to advantage, an advantage that a sustained release of the drug is obtained, which is further particles decompose in the body that can be administered to the implant by injection without incising the affected area It has been obtained advantage. However, in order to such microparticle formulation has to use organic solvents and reagents such as dichloromethane with toxicity, safety is a concern. Further, since the thus discharged from the particulate drug also together drawback capacitor for holding a drug is limited, and during removal cleaning of organic solvents such as dichloromethane used in the preparation for a fine, hold the particulates disadvantage amount of drug is reduced occurs newly.

Patent Document 3, drug and lactic-based polymer, ethanol, propanol, gel composition was dissolved in a lower alcohol such as isopropanol has been proposed. The gel composition has a high thixotropic property, and is like needle can pass, can be injected administered like a syringe. Lactic acid-based polymer in the administered gel is decomposed gradually drug with it also being sustained. With this composition, it is not necessary to use an organic solvent such as dichloromethane, and, holding the amount of the drug is also large. However, administration into the body of ethanol, stimulation, adverse effect on fertility or fetus, respiratory irritation, drowsiness and dizziness, fear of failure of liver disorders and central nervous system has been pointed out.

Patent Document 4 is insoluble in aqueous body fluid media or human or animal, is pharmaceutically acceptable, thermoplastic polymers that are biodegradable, are pharmaceutically acceptable, biodegradable, water-insoluble or water-slightly an organic solvent which is soluble, is pharmaceutically acceptable, adjuvants, and compositions comprising a bioactive agent has been proposed a are biocompatible and water soluble. The composition can be injected into the body by a syringe as a liquid composition to form a solid implant in situ in the body by exposure to body fluids. Therefore, the composition can be used as drug sustained release carrier. However, depending on the kind of the organic solvent, it not considered suitable for use in ocular tissue such as from the viewpoint of safety.

JP-T 2009-513493 JP JP 2007-146146 JP JP 2010-265277 JP JP-T 2008-523131 JP

The present invention allows a sustained release composition of the drug when included drugs, pourable into the body, such as a syringe, after injection, aims to provide a liquid composition solidifies in the body It is set to.

The present invention includes poly lactic acids and the solubilizing solvent, polylactic acids are dissolved in a solubilizing solvent, provides compositions and their preparation that can be injected into the body because it is liquid at room temperature to. Furthermore, drug and polylactic acids of polyethylene glycol (hereinafter, also referred to as PEG) by dissolving soluble solvent such as, provides an injectable sustained release compositions and their preparation. That is, the present invention,
<1> At least one of poly lactic acids and contain at least one of the solubilizing solvent, the liquid composition polylactic acids is dissolved in a solubilizing solvent;
<2> The polylactic acid compound is L- lactate, D- lactic acid, the composition according to <1> at least one of the monomers selected from glycolic acid;
<3> The composition according to the weight-average molecular weight comprising at least one poly lactic acids from 5,000 to 30,000 <1> or <2>;
<4> solubilizing solvent comprises at least one propylene glycol and polyethylene glycol <1> to A composition according to any one of <3>;
<5> as a solubilizing solvent, the composition according to <4> comprising at least one polyethylene glycol having a weight average molecular weight of 200-400;
<6> The weight ratio of the solubilizing solvent and polylactic acids are solubilized solvent / polylactic acids = 1 to 6 <1> - A composition according to any one of <5>;
The composition according to any one of <7> further containing a drug <1> to <6>;
<8> does not contain harmful substances to the human body, the composition according to any one of <1> to <7>;
<9> harmful substances to the human body, dichloromethane, ethanol, methanol or acetonitrile <8> The composition according; preparing and <10> <1> to the composition according to any one of <9> to a method, a mixture of poly lactic acids and solubilizing solvent, heated and polylactic acids and includes a step of dissolving the solubilizing solvent, does not include the step of using harmful substances to the human body, the Method;
I will provide a.

The compositions of the present invention can be administered without incising the affected area using a syringe. Administered composition solidifies in situ upon contact with body fluids in the body. Solidified composition can be retained long term at the site of administration, during which decomposes gradually, and finally disappears. Therefore, the inclusion of drug in the compositions of the present invention, which can release pharmaceutical obtain a drug for a long period of time. Moreover, since the composition of the present invention is lost, the drug and all the discharge, there is no need to remove the composition was solidified by incision site of administration again after finishing the role. Furthermore, without the use of organic solvents and reagents such as dichloromethane must finally removed in order to have a toxic, since the composition can be prepared by simply heating, in comparison to the likes of microparticle preparation, safety It is high. Moreover, since it is possible to prevent the leakage of the drug at the time of washing the organic solvent with a toxic, it is possible to increase the drug content in the composition.

Is a graph showing the drug release sustained into PBS. Is a photograph showing the retention of the shape and composition of the composition of the present invention was injected subcutaneously into rats. It shows the time course of release rate of MFLX into PBS.

[Poly lactic acids]
The polylactic acids used in the present invention, as long as pharmaceutically acceptable, may be used without particular limitation. Poly lactic acids of the present invention, the lactic acid only may be a homopolymer of the substrate, only the glycolic acid may be a homopolymer of a base, or a lactic acid and glycolic acid in the copolymer to the substrate it may be. Poly lactic acids of the invention may also contain minor amounts of comonomers effects of other long as not impaired the present invention. Examples of such comonomers, epsilon - caprolactone, and the like. Incidentally, the term "lactic acid" as used herein refers to L- lactate, D- lactic acid, DL- lactic acid and lactide, the term "glycolic acid" refers glycolic acid, glycolide.
Lactic acid-glycolic acid copolymers suitable for the present invention: the molar ratio of glycolic acid, 50: 50 ~ 85:15, especially 50: 50,75: 25,80: 20,85: 15 is preferred.
The weight average molecular weight of the poly lactic acids suitable for the present invention can be exemplified 3,000 to 150,000. Among them, if is preferably a weight average molecular weight using poly lactic acids of 5,000 to 100,000, more preferably 5,000 to 30,000, to form a more implanted easily compositions of the present invention. Weight average molecular weight is preferably comprises at least one poly lactic acids from 5,000 to 30,000. Especially, the weight average molecular weight of 5,000 to 20,000, poly lactic acids to the substrate of a copolymer of lactic acid and glycolic acid are preferred.
If polylactic acids used in the present invention are characteristic of the present invention can be obtained, even when used alone, it may be used by mixing several poly lactic acids.
Illustrative of polylactic acids to be added to pharmaceuticals, pharmaceutical additives Jiten 2007 (Japan Pharmaceutical Excipients Association editing, Yakujinipposha issued Inc.) according to, lactic acid-glycolic acid copolymer (1: 1), lactic acid- glycolic acid copolymer (95: 5) (high molecular weight copolymer), and lactic acid-glycolic acid copolymer (95: 5) (low molecular weight copolymer) and the like.

Poly lactic acids are generally for susceptible to hydrolysis by heating, in preparing the compositions of the present invention, it is preferable not to polylactic acids too much to the high temperatures used in the present invention. Further, as also it can be prepared in a water bath that can be used in conventional manufacturing equipment, the solubilizing solvent used in the present invention, those polylactic acids and can be uniformly dissolved at 100 ° C. or less. Further, when the composition of the present invention is injected into the body or water, by substitution of the solubilizing solvent and water in the compositions of the present invention (including the moisture contained in body fluids) occurs, poly lactic acids is since it solidifies in situ is a characteristic of the compositions of the present invention, the solubilizing solvent used in the present invention needs to have characteristics that may be substituted with water.
[Solubilizing solvent]
The solubilization solvent of the present invention is not particularly limited if the characteristics of the present invention is obtained preferably be exemplified polyethylene glycols and propylene glycol. Preferably, the solubilizing solvent comprises at least one propylene glycol and polyethylene glycol. Solubilizing solvent, if a solvent other than propylene glycol and polyethylene glycol is preferably those which do not adversely affect the human body. The solubilization solvent of the present invention, it is preferable to use only the polyethylene glycol.

Polyethylene glycol for use in the present invention can suitably be used are listed in the sixteenth Japanese Pharmacopoeia. For example, PEG-200, PEG-300, PEG-400, PEG-600, PEG-1000, PEG-1540, PEG-2000, PEG-4000, PEG-6000, PEG-20000, PEG-50000, PEG-500000, under the trade name of PEG-2000000 and PEG-4000000, it is available from Wako Pure Chemical Industries, Ltd.. In addition, the macro goal -200, macro goal -300, macro goal -400, macro goal -600, macro goal -1000, macro goal -1540, macro goal -4000, under the trade name of the macro goal -6000 and macro goal -20000 sold by Nippon Oil & Fats Co., Ltd..
The weight average molecular weight of the polyethylene glycol used in the present invention is not particularly limited if the characteristics of the present invention is obtained, preferably from 200 to 600, particularly preferably 200-400. If the weight average molecular weight of 600 or less is preferable because easily injected becomes liquid at room temperature.
Also, if the characteristics of the present invention is obtained, it is also possible to use a mixture of two or more of the PEG. Overview of PEG, standards, applications, about such as usage and product names, pharmaceutical additives Encyclopedia 2007 (Japan Pharmaceutical Additives Association editing, Yakujinipposha issued Co., Ltd.) are also described in detail.

The content of the polylactic acid compound and a solubilizing solvent in the compositions of the present invention, the compositions of the present invention to a liquid state, is not particularly limited as long as the effects expected for the present invention is obtained. The content of the polylactic acid compound in the composition of the present invention is usually 20 to 75 wt%, preferably 25 to 65 mass%, most preferably 33-50 wt%. The content of the solubilizing solvent in the compositions of the present invention, depending on the weight average molecular weight and the amount of the poly lactic acids to be used, usually 25 to 80 wt%, preferably 30 to 70 wt%, and most preferably 50-67 % by mass. The mass ratio of solubilizing solvent / polylactic acids in the compositions of the present invention is usually 0.3 to 10, preferably 1 to 6, more preferably 2 to 5, and most preferably 2-4.
The compositions of the present invention is a liquid at least 25 ° C..

The composition of the present invention, further may contain a drug. Such drugs, for example, amphotericin B, fluconazole, miconazole nitrate, sodium colistin methanesulfonate, carbenicillin sodium, gentamicin sulfate, erythromycin, azithromycin, tobramycin, kanamycin, ciprofloxacin hydrochloride, lomefloxacin hydrochloride, ofloxacin, levofloxacin, tosylate pazufloxacin, gatifloxacin, moxifloxacin hydrochloride, acyclovir, ganciclovir, cidofovir, sorivudine, anti-infective agents, such as trifluorothymidine, tetracyclines such as doxycycline, acitazanolast, levocabastine hydrochloride, ketotifen fumarate, cromoglycate sodium, antiallergic drugs such as tranilast, betamethasone phosphate, Dekisameta Emissions, hydrocortisone, diclofenac sodium c 厶, pranoprofen, triamcinolone acetonide, indomethacin, bromfenac sodium, meloxicam, lornoxicam, cyclosporine, anti-inflammatory agents such as tacrolimus, timolol maleate, bunazosin hydrochloride, latanoprost, nipradilol, carteolol hydrochloride , isopropyl unoprostone, glaucoma therapeutic agents, such as dorzolamide hydrochloride, brinzolamide, aminoethyl sulfonic acid, an amino acid, sodium chondroitin sulfate, sodium hyaluronate, irsogladine, corneal disorder or dry eye treatment such as tetracyclines, such as doxycycline, Pega of descriptor nib sodium, ranibizumab, aflibercept, anti-VEGF drugs such as bevacizumab, candesartan Azilsartan can include telmisartan, losartan, and the like angiotensin II receptor antagonists such as azilsartan. The content in the composition of the present invention, these drugs are not particularly limited as long as it is a concentration of efficacy to be expected can be obtained. For example, in the composition is about 0.01 to 10 wt%.

The composition of the present invention, a buffer as needed In addition, isotonic agents, pH adjusting agents, stabilizing agents, preservatives, solubilizing agents and additives such as thickeners, the effect of the present invention it can be added within a range that does not impair the.

The compositions of the present invention can be prepared without the use of harmful substances to the human body. The harmful substances to the human body, for example, dichloromethane, ethanol, methanol or acetonitrile and the like.

Next, describing an example of the preparation of the compositions of the present invention. A predetermined amount of poly lactic acids were weighed in a beaker, where applying a predetermined amount of solubilized solvent. Warmed in a water bath (preferably 100 ° C. or less), by dissolving polylactic acids, and stirred until homogeneous, to obtain a composition of the present invention. If further contain drug in the compositions of the present invention, the drug may be added after dissolution of even or polylactic acids are added together with polylactic acid, dissolved or dispersed, and stirred until homogeneous, the yield a composition of the invention. The compositions of the present invention was charged to a predetermined dose vials may be a product by sterilizing in an autoclave.

Methods of using the compositions of the present invention is not particularly limited, for example, intramuscular injection, intraarticular injection, soft tissue injection, tendons injection, intrasynovial injection, epidural injection, intraperitoneal injection, topical intradermal injection, subconjunctival injection, intranasal injection, sub intranasal instillation, nasal turbinates injection, nasal polyps injection, middle ear cavity injection, subcutaneous injection, intravitreal injection, scleral injection, tenon intracisternal injection or punctum such as the internal injection, and the like. The compositions of the present invention may also, after molding in water, can be used by embedding in the body.

Hereinafter, the present invention will be described in detail, the present invention is not limited thereto.

Example 1 to 12
As polylactic acids, using the product manufactured by Taki Chemical Co., Ltd. below.
· DLG-80 DL-lactic acid - glycolic acid copolymer (molar ratio of D- lactic acid and L- lactic acid 1: 1, lactic acid content of 80 mol%)
The weight average molecular weight 05,000, 10,000, 20,000, 30,000, 50,000 · DLG-50 DL-lactic acid - glycolic acid copolymer
(Molar ratio of D- lactic acid and L- lactic acid 1: 1, lactic acid content of 50 mol%)
Weight average molecular weight of 10,000 · L-100-100 L-lactic acid 100% polymer weight average molecular weight of 100,000 solubilizing solvent was used the product shown below.
· PEG300,400 manufactured by Wako Pure Chemical Industries, polyethylene glycol 300, 400

Beaker predetermined amounts of poly-lactic acids was added a predetermined amount of solubilized solvents here. It was warmed in a water bath at 80 ~ 90 ° C., poly lactic acids is dissolved in a solubilizing solvent, and stirred with a magnetic stirrer until uniform. Then, allowed to cool to room temperature to obtain a composition of the present invention (Examples 1-10).

Test Example 1 (Evaluation of retention at the injection property and in PBS into the phosphate buffered saline of the compositions of the present invention (PBS))
The compositions of the present invention obtained in Examples 1-10, was 0.5mL filled into locking plastic syringe 2.5 mL. A predetermined needle (21, 27 or 30 gate - di) fitted with, in screw cap vial containing the PBS of 5 mL, while immersing the needle in PBS, slowly compositions 0.1mL of the present invention injected. The composition of the present invention was injected into PBS immediately solidified milky, it becomes ribbon or bulk, settled on the bottom of the vial. Then, the lid to the vial, and stored at 37 ℃. After 24 hours, the PBS in vials, the composition of the present invention as solidification taking care not washed away, and the total amount discarded. Here, adding fresh PBS 5 mL had been warmed to separate 37 ° C.. PBS discarded and additional, the compositions of the present invention was solidified in vials repeated every 24 hours until complete decomposition disappeared was recorded the number of months taken until disappearance at 0.5 months units.

Table 1, the composition of the compositions of the present invention, showing the time to gauge needle used during injection into PBS, the compositions of the present invention from the PBS at 37 ° C. decomposes disappeared.
Polylactic acids used in the preparation of the compositions of the present invention were all shown to dissolve the solubilized solvent at 100 ° C. or lower. Also, syringability any composition, it pourable is shown. Further, when the composition of the present invention was injected into PBS, by replacement of the water and solubilizing solvent, poly lactic acids in the composition have been shown to solidify. The composition solidified gradually decomposed in PBS for 37 ° C., after staying 0.5-2 months of long-term, it was shown to completely disappear.

Figure JPOXMLDOC01-appb-T000001

Example 11
Beaker, a DLG-50 (weight average molecular weight: 10,000) 0.6 g, was put irsogladine 0.03 g. Here, the PEG-400 was added 0.5 g. This immersed warmed in a water bath at 80 ~ 90 ° C., and dissolved in PEG-400 is DLG-50 and irsogladine, and stirred with a magnetic stirrer until uniform. Then, allowed to cool to room temperature to obtain compositions of the present invention (Example 11).

Test Example 2 (persistence evaluation of drug release into PBS in the compositions of the present invention)
The compositions of the present invention obtained in Example 11 was 0.5mL filled into locking plastic syringe 2.5 mL. Then, the injection needle 23 gauge its syringe mounting, the screw cap vials containing PBS for 5 mL, while immersing the needle in PBS, the composition of the present invention was 0.1mL slowly injected. The composition of the present invention was injected into the PBS immediately solidified milky, settled on the bottom of the vial. Then, the lid to the vial, and stored at 37 ℃. After one week, the PBS in the vial, being careful composition of the present invention which solidified is not washed away, and 1mL collected. Into a vial, adding fresh PBS 1 mL had been warmed to separate 37 ° C.. PBS of the collection and the additional was repeated 16 weeks every week. The irsogladine concentration in PBS of the collected 1mL was measured by HPLC.

Figure 1 shows the density change of irsogladine in PBS. It was almost constant drug concentration from the initial stage up to 14 weeks. Every despite drug concentration is taken PBS is constant Nanoha, only the amount of drug removed from PBS in vials by taking the PBS, that the drug is slowly released into the PBS in the solidified composition shows.

Example 12
Beaker was put DLG-80 (weight average molecular weight 10,000) 3 g. The PEG-300 was added 6g here. This immersed warmed in a water bath at 80 ~ 90 ° C., to dissolve DLG-80 is a PEG-300, and stirred with a magnetic stirrer until uniform. Then, allowed to cool to room temperature to obtain a composition of the present invention. This was filled in vials of 20mL. After sealed, conducted autoclave sterilization, and allowed to cool.
This was 2.5mL aseptically filled into locking plastic syringes 2.5mL. And, it was fitted with a needle of 21 gauge on the syringe.

Test Example 3 (retention irritating Evaluation of the compositions of the present invention by subcutaneous administration in rats)
The composition 0.5mL of the present invention obtained in Example 12 was administered to cervical subcutaneously in rats (BN / CrlCrlj line, male). After 1 day and after 14 days of administration, dissected neck skin of the administration site, the degree of the remaining of the composition of the solidified Example 12, to confirm the shape and presence or absence of inflammation subcutaneously with the naked eye. Also, blood was collected in rats after 14 days of administration, alkaline phosphatase in serum were carried out blood biochemical examination for leucine aminopeptidase and creatine phosphokinase.

Figure 2 shows the shape of the compositions of the present invention at the site of administration after 1 day and after 14 days of administration. The compositions of the present invention, solidified after subcutaneous administration was shown to stay at the site of administration. The size of the compositions of the present invention in one day after the administration 14 days after administration, apparently large difference was not seen. Therefore, the compositions of the present invention have been shown to remain at the site of administration over an extended period of time after administration. Also, apparently, adverse events such as inflammation was not observed. Furthermore, even in the blood biochemical examination results after 14 days of administration, no difference compared to the untreated group as a control, the compositions of the present invention have been shown to be safe.
From the above results, the compositions of the present invention, it capable of administration by injection, it is solidified at the site of administration after the administration, it stays a long time at the site of administration, and safety have been shown to be very high . Referring to FIG. 2.

Formulation Example 1 (punctum infusion agent)
The composition 1mL of the present invention comprising irsogladine prepared in the same manner as in Example 11 was filled into vials 10 mL. After sealed, conduct autoclave sterilization, allowed to cool and the punctum infusion agent.
In administration to the punctum, it is used the compositions of the present invention from the vial, such as a syringe aseptically transferred.

Formulation Example 2 (intramuscular injection, intraarticular injection, soft tissue injections, tendon injection agent, intrasynovial infusion, epidural injection, intraperitoneal injection, topical intradermal injection, subconjunctival injection, intranasal infusion, paranasal cavity infusion, nasal turbinates in injections, nasal polyps in injections, middle ear cavity infusion, subcutaneous injection)
The DLG-80 (weight average molecular weight 10,000) 3 g and dexamethasone 0.1 g, was added PEG-300 6 g. Warmed soaked it in water bath at 80 ~ 90 ° C., to dissolve DLG-80 and dexamethasone in PEG-300, and stirred with a magnetic stirrer until uniform. Then, allowed to cool to room temperature to obtain a composition of the present invention. The 2mL filling into the vial of 10 mL. After sealed, conduct autoclave sterilization, allowed to cool, intramuscular injection, intraarticular injection, soft tissue injections, tendon injection agent, intrasynovial infusion, epidural injection, intraperitoneal infusion , local intradermal injection, subconjunctival injection, intranasal infusion, paranasal cavity infusion, nasal turbinates in injections, nasal polyps in injections, and the middle ear cavity infusion or subcutaneous injection.
In administration, it is used the compositions of the present invention from the vial, such as a syringe aseptically transferred.

Formulation Example 3 (vitreous injection, scleral infusion, Tenon's sac infusion)
DLG-80 (weight average molecular weight 20,000) 1 g, the DLG-50 (weight average molecular weight 10,000) 2 g and triamcinolone acetonide 0.1 g, was added PEG-300 6 g. This immersed warmed in a water bath at 80 ~ 90 ℃, DLG-80 and DLG-50 and triamcinolone acetonide are dissolved in PEG-300, and stirred with a magnetic stirrer until uniform. Then, allowed to cool to room temperature to obtain a composition of the present invention. The 2mL filling into the vial of 10 mL. After sealed, conduct autoclave sterilization, allowed to cool, vitreous injection and a scleral infusion or Tenon's sac infusion.
In administration, it is used the compositions of the present invention from the vial, such as a syringe aseptically transferred.

Formulation Example 4 (vitreous injections, Tenon's sac infusion)
DLG-80 (weight average molecular weight: 10,000) 1 g and DLG-50 (weight average molecular weight: 10,000) 1 g, candesartan cilexetil 0.2 g, was added PEG-300 4g. This immersed warmed in a water bath at 80 ~ 90 ° C., and dissolved in DLG-80 and candesartan cilexetil PEG-300, and stirred with a magnetic stirrer until uniform. Then, allowed to cool to room temperature to obtain a composition of the present invention. The 1mL filling into the vial of 10 mL. After sealed, conduct autoclave sterilization, allowed to cool and the vitreous injection and Tenon's sac infusion.
In administration, it is used the compositions of the present invention from the vial, such as a syringe aseptically transferred.

Formulation Example 5 (intramuscular injection, intraarticular injection, vitreous injection, Tenon's sac infusion)
The DLG-80 (weight average molecular weight 10,000) 2 g and Diclofenac sodium 0.2 g, was added PEG-300 4g. This immersed warmed in a water bath at 80 ~ 90 ℃, DLG-80 sodium diclofenac are dissolved in PEG-300, and stirred with a magnetic stirrer until uniform. Then, allowed to cool to room temperature to obtain a composition of the present invention. The 1mL filling into the vial of 10 mL. After sealed, conduct autoclave sterilization, allowed to cool, intramuscular injection, intraarticular injection, and a vitreous injection or Tenon's sac infusion.
In administration, it is used the compositions of the present invention from the vial, such as a syringe aseptically transferred.

Examples 13-52
As polylactic acids, using the product manufactured by Taki Chemical Co., Ltd. below.
· DLG-80 DL-lactic acid - glycolic acid copolymer (molar ratio of D- lactic acid and L- lactic acid 1: 1, lactic acid content of 80 mol%)
The weight average molecular weight 05,000, 10,000, 20,000 · DLG-50 DL-lactic acid - glycolic acid copolymer
(Molar ratio of D- lactic acid and L- lactic acid 1: 1, lactic acid content of 50 mol%)
The weight average molecular weight of 10,000 · DG-80 D- lactic - glycolic acid copolymer (lactic acid consists only D- lactic acid,
It does not include the L- lactic acid.
Lactic acid content 80 mol% is)
The weight average molecular weight of 10,000 · LG-80 L- lactic - glycolic acid copolymer (lactic acid consists only L- lactic acid,
It does not include the D- lactic acid.
Lactic acid content 80 mol% is)
Weight average molecular weight of 10,000

As a solubilizing solvent, and using the products shown below.
· PEG300,400 manufactured by Wako Pure Chemical Industries, polyethylene glycol 300, 400

Beaker predetermined amounts of poly-lactic acids was added a predetermined amount of solubilized solvents here. It was warmed in a water bath at 80 ~ 90 ° C., poly lactic acids is dissolved in a solubilizing solvent, and stirred with a magnetic stirrer until uniform. Then, allowed to cool to room temperature to obtain a composition of the present invention (Examples 13 to 54).

Test Example 4 (evaluation of retention at the injection property and in PBS into PBS in the compositions of the present invention)
The compositions of the present invention obtained in Examples 13 to 51 and 0.5mL filled into locking plastic syringe 2.5 mL. Then, mounting the injection needle 18 gauge its syringe, a screw cap vial containing the PBS of 5 mL, the injection needle without immersed in PBS, it was added dropwise a composition of the present invention a drop slowly. The composition of the present invention was dropped into the PBS immediately solidified milky, becomes massive, it settled on the bottom of the vial.
Then, the lid to the vial, and stored at 37 ℃. Week five times (at intervals of minimum of 24 hours), being careful composition of the present invention which solidified is not washed away, the PBS in the vial bottle was 4mL discarded. Into a vial, adding fresh PBS 4 mL had been warmed to separate 37 ° C.. PBS discarded and additional, repeated until the composition of the present invention in the vial is completely decomposed disappeared was recorded the time taken for degradation disappearance weekly.

Table 2-8, the composition of the compositions of the present invention obtained in Examples 13 to 51 The composition of the present invention from the PBS at 37 ° C. showed the time until the decomposition loss.
Polylactic acids used in the preparation of the compositions of the present invention were all shown to dissolve the solubilized solvent at 100 ° C. or lower. Also, syringability any composition, it pourable is shown. Further, when the composition of the present invention was dropped into PBS, by substitution of solubilization solvent in the composition of the water and the present invention in PBS, it is shown that poly lactic acids in the compositions of the present invention is solidified It has been. The compositions of the present invention which solidified gradually decomposed in PBS for 37 ° C., after long-term retention of 2-9 weeks, to be completely disappeared shown.
Moreover, it was shown that there is generally a tendency as follows for the rate of degradation of the composition and in the PBS of the compositions of the present invention.
· The lactic acid of the optically active poly lactic acids slow decomposition of D- lactic acid, then L- lactic acid, the decomposition of inclusions D- lactic acid and L- lactic acid was fast.
Decomposition and the molar ratio of lactic acid and glycolic acid for about a molar ratio of lactic acid is high was slow.
- molecular weight of the poly lactic acids for higher weight average molecular weight of the poly lactic acids is high decomposition was slow.
Mass ratio of the polylactic acid compound and PEG (solubilizing solvent) for about the content of the polylactic acid compound often degradation was slow.
As described above, to prepare a mass ratio type and solubilizing solvent polylactic acid, etc. is used, it is possible to control the degradation rate of the poly lactic acids was demonstrated. Than this, when incorporated drug into the composition of the present invention, since the sustained release of the drug will depend on the degradation of polylactic acids, it is also possible to control the release rate of the drug.

Figure JPOXMLDOC01-appb-T000002

Figure JPOXMLDOC01-appb-T000003

Figure JPOXMLDOC01-appb-T000004

Figure JPOXMLDOC01-appb-T000005

Figure JPOXMLDOC01-appb-T000006

Figure JPOXMLDOC01-appb-T000007

Figure JPOXMLDOC01-appb-T000008

Example 52 DLG-80 (weight average molecular weight: 10,000) 0.2 g and moxifloxacin hydrochloride (hereinafter, abbreviated as MFLX) to 0.02 g, was added PEG300 0.4 g. This immersed warmed in a water bath at 80 ~ 90 ° C., and dissolved in PEG-300 is DLG-80 and MFLX, and stirred with a magnetic stirrer until uniform. Then, allowed to cool to room temperature to obtain compositions of the present invention (Example 52).

Test Example 5 (persistence evaluation of drug release into PBS in the compositions of the present invention)
The compositions of the present invention obtained in Example 52 was filled into locking plastic syringe 2.5 mL. Then, an injection needle 21 gauge its syringe mounting, the screw cap vial containing the PBS of 5 mL, while immersing the needle in PBS, the composition of the present invention was 0.1mL slowly injected. The composition of the present invention was injected into PBS is immediately solidified milk pale yellow, settled on the bottom of the vial. Then, the lid to the vial, and stored at 37 ℃. Storage 1,3,8,14,21,28,35,42 and 49 days after the PBS in vials, the composition of the present invention the solidified was 4mL collected taking care not washed away. Into a vial, adding fresh PBS 4 mL had been warmed to separate 37 ° C.. The MFLX concentration in PBS of the collected 4mL was measured by HPLC.
Figure 3 shows the time course of release rate of MFLX into PBS. Release rate was determined in the following manner.

Release rate (%) = (MFLX weight was injected in PBS MFLX total / first released in PBS) × 100

Injection 1 day after, about half the amount of MFLX added was released into the PBS. This is when the solubilizing solvent (PEG-300) and PBS is substituted for the compositions of the present invention, it is believed that part of MFLX was released in PBS with solubilizing solvent. Thereafter, MFLX substantially constant speed until after injection 49 days is released, the drug was shown to be sustained for a long period of time.

The compositions of the present invention, when containing a drug, can be used as pharmaceuticals. Can be administered as a general injection, since it is possible to release the drug over a prolonged period of time at the site of administration, without frequent administration is a pharmaceutical which can be expected long-term therapeutic effect. Also, high safety, all ultimately is a pharmaceutical that does not need to take out after the treatment since the lost in vivo. Furthermore, manufacturing is simple, without using harmful substances in the production, adaptable to many drugs, a drug holding amount is also large pharmaceuticals.

Claims (10)

  1. At least one of polylactic acids and contain at least one of the solubilizing solvent, the liquid composition polylactic acids is dissolved in a solubilizing solvent.
  2. Polylactic acids are L- lactic, D- lactic acid composition of claim 1, monomer at least one selected from glycolic acid.
  3. A composition according to claim 1 or 2 weight-average molecular weight of at least one poly lactic acids from 5,000 to 30,000.
  4. A composition according to any one of claims 1 to 3, solubilizing solvent comprises at least one propylene glycol and polyethylene glycol.
  5. As a solubilizing solvent composition of claim 4 comprising at least one polyethylene glycol having a weight average molecular weight of 200-400.
  6. Weight ratio of the solubilizing solvent and polylactic acids are solubilized solvent / polylactic acids = 1 ~ composition according to any one of claims 1 to 5, which is a 6.
  7. A composition according to any one of claims 1 to 6, further containing a drug.
  8. Does not contain harmful substances to the human body, the composition according to any one of claims 1 to 7.
  9. Materials deleterious to the human body, dichloromethane, ethanol, composition according to claim 8, wherein methanol or acetonitrile.
  10. A method of preparing a composition of any one of claims 1-9, poly lactic acids and the solubilizing solvent were mixed and dissolved polylactic acids the solubilization solvent by heating step but it does not include the step of using harmful substances to the human body including, the methods.
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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5607686A (en) * 1994-11-22 1997-03-04 United States Surgical Corporation Polymeric composition
WO1999021908A1 (en) * 1997-10-29 1999-05-06 Angiotech Pharmaceuticals, Inc. Polymeric systems for drug delivery and uses thereof
JP2003517886A (en) * 1999-12-22 2003-06-03 サムヤン コーポレイション Liquid compositions of the drug delivery system for biodegradable block copolymer and a method of manufacturing
JP2008501757A (en) * 2004-06-09 2008-01-24 ノバルティス アクチエンゲゼルシャフト Pharmaceutical compositions comprising a polyethylene glycol having a molecular weight of less than 600 Daltons
JP2011530568A (en) * 2008-08-12 2011-12-22 ノバルティス アーゲー Pharmaceutical compositions

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5607686A (en) * 1994-11-22 1997-03-04 United States Surgical Corporation Polymeric composition
WO1999021908A1 (en) * 1997-10-29 1999-05-06 Angiotech Pharmaceuticals, Inc. Polymeric systems for drug delivery and uses thereof
JP2003517886A (en) * 1999-12-22 2003-06-03 サムヤン コーポレイション Liquid compositions of the drug delivery system for biodegradable block copolymer and a method of manufacturing
JP2008501757A (en) * 2004-06-09 2008-01-24 ノバルティス アクチエンゲゼルシャフト Pharmaceutical compositions comprising a polyethylene glycol having a molecular weight of less than 600 Daltons
JP2011530568A (en) * 2008-08-12 2011-12-22 ノバルティス アーゲー Pharmaceutical compositions

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