WO2014108076A1 - Composition de gel de médicament insoluble et son procédé de préparation - Google Patents

Composition de gel de médicament insoluble et son procédé de préparation Download PDF

Info

Publication number
WO2014108076A1
WO2014108076A1 PCT/CN2014/070369 CN2014070369W WO2014108076A1 WO 2014108076 A1 WO2014108076 A1 WO 2014108076A1 CN 2014070369 W CN2014070369 W CN 2014070369W WO 2014108076 A1 WO2014108076 A1 WO 2014108076A1
Authority
WO
WIPO (PCT)
Prior art keywords
poorly soluble
drug
gel composition
pharmaceutical gel
solvent
Prior art date
Application number
PCT/CN2014/070369
Other languages
English (en)
Chinese (zh)
Inventor
张强
代文兵
林志强
王学清
Original Assignee
北京大学
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 北京大学 filed Critical 北京大学
Publication of WO2014108076A1 publication Critical patent/WO2014108076A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K47/34—Macromolecular 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner

Definitions

  • the present application relates to a poorly soluble pharmaceutical gel composition and a process for the preparation thereof, which belong to the field of pharmaceutical preparations.
  • nanocrystal refers to drug solid particles with nanometer scale, also known as nanocrystals or nanocrystals. If the drug nanocrystals are dispersed in a suitable liquid medium, a nanosuspension can be formed. Generally, the nanometer-sized drug particles can be dispersed in water by the stabilization of the surfactant or the polymer material, thereby forming a relatively stable colloidal dispersion system.
  • a series of oral nano-drugs have been developed at home and abroad for the problem of low oral bioavailability of poorly soluble drugs. These poorly soluble drugs have been prepared into nanocrystalline drugs through special techniques. Studies have shown that this can significantly improve the poor solubility.
  • nanocrystals are used for injection or topical administration (such as the eyes, nasal cavity, etc.), it can solve the problem that poorly soluble drugs cannot be made into liquid preparations due to poor solubility, and it is possible to produce local sustained release. The effect, thereby prolonging the duration of action of the drug.
  • the saturation solubility is affected by the particle size, the solubility of small particles is large, and the solubility of large particles is small. As a result, small particles gradually dissolve and large particles gradually become larger. This phenomenon is called austenitic ripening. (Ostwald ripening ).
  • drug nanocrystals may also have problems such as sedimentation and agglomeration during their preparation, storage, and transportation. Therefore, how to improve the stability of drug nanocrystals is also a difficult problem to be solved by pharmacy.
  • Temperature-sensitive gels are a class of gel systems prepared from temperature-sensitive, intelligent polymers that undergo a phase transition with temperature to form a non-chemically crosslinked gel.
  • the liquid state is exhibited because the ambient temperature is lower than the lowest critical phase transition temperature (LCST) of the gel, and the semi-solid gel state is exhibited when the temperature of the drug site is higher than the LCST.
  • LCST critical phase transition temperature
  • the injection enters the human body a phase transition can be rapidly formed at the injection site to form a semi-solid gel, thereby prolonging the residence time of the drug at the site of administration after local administration, and achieving a good sustained release effect.
  • temperature Sensitive gels are attractive as topical formulations, including topical administration to tumors (such as intratumoral or peritumoral injections) and ocular administration.
  • the sustained release effect after local injection is within 10 days, and the current polymer microsphere technology can achieve a sustained release effect of more than one month.
  • gelling agents have more advantages than polymer microsphere preparations in terms of preparation, quality control and cost. Therefore, it would be of great practical significance to prepare a temperature-sensitive gelling agent with a sustained release of more than one month.
  • the gel is mostly hydrophilic, for the poorly soluble drug, when the temperature sensitive gel is prepared, the drug loading amount is insufficient, or some drugs are present in the gel in a suspended form, the drug dispersion is uneven, and the release rate is high. It is not easy to control, thus affecting the exertion of the drug effect.
  • surfactants can be added to increase the drug loading, but the amount of the drug is large, a large number of surfactants bring new problems such as toxic side effects, and surfactants cannot solve or even aggravate the existing medicinal temperature-sensitive coagulation. The problem of releasing the drug faster.
  • Cispray No. CN102579323 discloses a paclitaxel plastid gel which is formed by uniformly mixing an alcoholic substance of paclitaxel and a hydrophilic gel, and is mainly used for transdermal administration of a drug, preferably It promotes the percutaneous absorption of the drug and can reduce the irritating effect of the preparation on the skin.
  • the patent publication CN101336891 discloses an anticancer sustained release gel injection and a preparation method thereof, which are prepared by mixing a solution of an anticancer drug or an anticancer drug directly with an aqueous solution of an amphiphilic copolymer.
  • CN101342142 discloses a gel injection for a taxane anticancer drug and a preparation method thereof, which are characterized in that a taxane anticancer drug is firstly solubilized with a surfactant and then reacted with a temperature sensitive copolymer. Prepared by mixing.
  • the purpose of the present application is to provide a poorly soluble pharmaceutical gel composition to overcome the technical problems of poor physical stability of the drug nanocrystal, low drug loading of the general temperature sensitive gel, and short drug release time.
  • a poorly soluble pharmaceutical gel composition comprising: a drug nanocrystal of a poorly soluble drug, a stabilizer, a temperature sensitive material, and a vehicle.
  • the poorly soluble drug may be selected from the group consisting of paclitaxel, docetaxel, camptothecin, 9-hydroxycamptothecin, 10-hydroxycamptothecin, itraconazole, teniposide, backing Botulin, cyclosporine A, doxorubicin, capecitabine, oxaliplatin, irinotecan, gemcitabine, temozolomide, imatinib, vinorelbine, letrozole, vinblastine, vincristine, Vindesine, Vinpocetine, Deinhibitor, Silybin, Artemisinin, Dihydroartemisinin, Sirolimus, Nitrendipine, Nicardipine, Nimodipine, Breviscapine , ferulic acid, acetaminophen, vitamin A, tamoxifen, valproic acid, tacrolimus, fenofibrate, amphotericin B, ketoconazole, domperi
  • the stabilizer may be selected from the group consisting of Tween-80, sodium lauryl carbonate (SDS), polyoxyethylene hydrogenated castor oil, omega ester, polyethylene glycol, poloxamer, hydroxypropyl hydrazine Cellulose (HPMC), povidone, polyethylene glycol vitamin E succinic acid (TPGS), cholic acid, sodium cholate, sulfhydryl cellulose (MC), hydroxypropyl cellulose (HPC) or polyvinyl alcohol (PVA) One or more of them.
  • the stabilizer may be selected from one or more of poloxamer, polyethylene glycol vitamin E succinic acid or sodium lauryl sulfate.
  • the temperature sensitive material may be selected from the group consisting of poloxamer, polylactic acid-polyethylene glycol-polylactic acid, polyglycolide lactide-polyethylene glycol-polyglycolide lactide. , polyethylene glycol-polylactic acid-polyethylene glycol, polyethylene glycol-polyglycolide lactide-polyethylene glycol, polycaprolactone-polyethylene glycol-polycaprolactone or chitosan One or more of them.
  • the temperature sensitive material may be a poloxamer.
  • the vehicle may be selected from one or more of water, physiological saline, 5% dextrose solution, glycerol, polyethylene glycol, propylene glycol, ethanol.
  • the solvent may be water, and preferably, the solvent may be purified water, and more preferably, the solvent may be a note.
  • Shoot water may be water, and preferably, the solvent may be a note.
  • the poloxamer may be one or both of poloxamer 407 (trade name: Pluronic F127) and poloxamer 188 (trade name: Pluronic F68).
  • Polymers such as polyethylene glycol, polylactic acid, polyglycolide lactide, polycaprolactone and the like as stabilizers or temperature sensitive materials in the present application may include different molecular weights. As will be appreciated by those skilled in the art, the molecular weight of the polymers will not significantly alter their role in the present invention, with most of the polymers used in this application being commercially available.
  • the weight ratio of the stabilizer to the poorly soluble drug may be from 1:20 to 50:1, preferably from 1:5 to 5:1.
  • the sum of the weight of the stabilizer and the poorly soluble drug may range from 0.001% to 20%, preferably from 0.05% to 5%, based on the total weight of the entire poorly soluble pharmaceutical gel composition.
  • the sum of the weight of the stabilizer and the poorly soluble drug may be from 0.008% to 10%, preferably from 0.04% to 3% of the total weight of the entire poorly soluble pharmaceutical gel composition. %.
  • the weight ratio of the temperature sensitive material to the solvent may be 1:10 to 1.5:1, preferably 1:5-3. : 5.
  • the particle size of the drug nanocrystal of the poorly soluble drug may range from 20 to 600 nm, preferably from 100 to 300 nm. It should be noted that the particle size described herein is the average particle size measured by a commercially available laser particle size analyzer, rather than the long or short diameter of the drug nanocrystals observed under electron microscopy.
  • the present application also provides a method of preparing the above poorly soluble pharmaceutical gel composition, the method comprising the steps of:
  • the method can include the following steps:
  • the temperature sensitive material is added to the solvent, stirred under a water bath, and after the temperature sensitive material is completely dissolved, a blank gel B is obtained;
  • the organic solvent may be selected from one or more of the group consisting of dichloromethane, chloroform, anhydrous ethanol, decyl alcohol, acetonitrile, propylene glycol, ethyl acetate, and petroleum ether.
  • a poorly soluble drug is prepared as a suspension of a drug nanocrystal by the above method
  • the preparation of the drug nanocrystal (or a suspension thereof) can also be accomplished by the skill or person.
  • Preparation of drug nanocrystals by well-known Top-down methods or Bottom-up methods, such as wet milling, co-evaporation or anti-solvent methods [Chavhan SS, Petkar KC, Sawant KK. Nanosuspensions in drug delivery: recent advances, patent scenarios , and commercialization aspects. Crit Rev Ther Drug Carrier Syst. 2011;28(5):447-88.].
  • the residual organic solvent can be further removed by conventional operations such as vacuum drying.
  • additives such as pH adjusters, bacteriostatic agents, antioxidants, osmotic pressure regulators, and the like may be further added to the compositions of the present application as needed.
  • Additives, etc. include lactose, glucose, glycerin, MC, HPMC, PVA, and sodium alginate. These additives can be used to adjust the gelation temperature and viscosity of the gel. Degree, bioadhesiveness, release rate, etc., it should be noted that the above additives such as MC, PVA, HPMC, etc. can also function as stabilizers.
  • the present application further provides the above-mentioned poorly soluble pharmaceutical gel composition in intratumoral injection, peritumoral injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, interventional treatment, postoperative administration, ocular medication or nasal medication. Application in .
  • the amount of stabilizer used in the present application is extremely small.
  • the sum of the weight of the stabilizer and the poorly soluble drug is only 0.008%-10% of the total weight of the entire poorly soluble pharmaceutical gel composition. It eliminates hidden dangers such as allergies caused by solubilized surfactants in commercially available poorly soluble drug injections, and improves the safety of drugs.
  • the physical stability of the drug nanocrystals in the poorly soluble pharmaceutical gel composition provided by the present application is significantly improved compared to the single drug nanocrystal composition, especially the long-term storage stability is remarkably improved.
  • the poorly soluble drug gel composition provided by the present application can significantly delay the drug release time, thereby prolonging the action time of the drug and improving treatment effect.
  • the poorly soluble pharmaceutical gel composition provided by the present application can increase the drug loading of the poorly soluble drug and avoid the occurrence of long-term storage. Problems such as drug deposition improve the needle-forming properties of the injection, and improve the uniformity of drug distribution and release.
  • FIG. 1 is a particle size distribution diagram (A, C) and a transmission electron micrograph (B, D) of paclitaxel nanocrystals in a paclitaxel nanocrystal and a paclitaxel nanocrystal gel composition in a paclitaxel nanocrystal suspension of Example 1.
  • 2 is an in vitro release profile of the paclitaxel nanocrystalline gel composition of Example 1;
  • FIG. 3 is a comparison of the paclitaxel nanocrystals in the paclitaxel nanocrystal suspension of Example 1 and the paclitaxel nanocrystals in the paclitaxel nanocrystalline gel composition.
  • Fig. 4 Tumor volume-time change pattern of BALB/c mice bearing 4T1 tumors in each administration group after intratumoral administration;
  • Fig. 5 is a graph showing changes in body weight of BALB/c mice bearing 4T1 tumors in each administration group after intratumoral administration;
  • Fig. 7 Changes in body weight of mice bearing MCF-7 tumors in each administration group after intratumoral administration.
  • the dried chloroform was removed by drying in a vacuum oven at 25 ° C for 12 hours to obtain a dried paclitaxel and a Plenix F127 film.
  • 8 ml of purified water was added to the above dried paclitaxel and Pluronic F127 film, and rotary evaporation was continued in a RE52CS-1 rotary evaporator, hydrated for 40 min, and vortexed in a WH-861 vortex mixer (Taicang Science and Education Equipment Factory). After spinning for 10 min, the vortex speed was 2400 rpm, and then ultrasonication was carried out for 15 min at 100 W in a KQ-100DE ultrasonic cleaner to obtain a uniform transparent paclitaxel nanocrystal suspension.
  • the particle size of the drug solid particles in the suspension of paclitaxel nanocrystals and the finally obtained paclitaxel nanocrystalline gel composition was measured, and a transmission electron micrograph was taken, as follows: Prepared in Example 1 The paclitaxel nanocrystal suspension and the paclitaxel nanocrystalline gel composition were diluted 10 times and 100 times with purified water, respectively, and the particles at 25 ° C were measured using a Malvern laser particle size analyzer (Zetasizer 3000HS, Malvem, UK). Path (results shown in A and C in Figure 1).
  • the paclitaxel nanocrystal suspension was diluted 10 times with purified water, and the paclitaxel nanocrystal gel composition was diluted 100 times with purified water, and its structure was observed by a transmission electron microscope (JEM-200X, JEOL, Japan) (results as shown in Fig. 1) B and D)).
  • the specific operation is as follows: After the diluted sample is kept at room temperature (20 °C) for 30 min, it is added dropwise to the copper mesh of the carbon coated film, and after the water is volatilized, it is directly added to the JEM-200X transmission electron microscope to observe the acceleration voltage. 80kv.
  • the results of the laser particle size analyzer showed that the nanocrystal particle diameter in the suspension of paclitaxel nanocrystals was 120 nm, and the drug solid particle diameter of the paclitaxel nanocrystal gel composition was 156 nm.
  • the results of transmission electron microscopy showed that the nanocrystals in the paclitaxel suspension were short rod-like structures with a particle size of 100-200 nm. After loading the Pluronic F127 gel, they still existed in the form of nanocrystalline short rods with a particle size of 100- Between 200nm. The results observed by transmission electron microscopy were consistent with those obtained by laser particle size analyzer.
  • the particle size of the drug solid particles in the suspension of the poorly soluble drug nanocrystals prepared in the other examples and the poorly soluble drug nanocrystal gel composition was measured by a Malvern laser particle size analyzer, and the results showed All drug nanocrystals have a particle size of less than 600 nm and most of the particle size is between 100 and 300 ⁇ .
  • the instrument Vortex Science and Education Equipment Factory
  • vortex speed is 2400 rpm
  • ultrasonic cleaner ultrasonic lOmin at 100W
  • Example 4 Preparation of Camptothecin Nanocrystalline Gel Composition 1.
  • camptothecin and 12 mg of stabilizer polyethylene glycol vitamin E succinic acid (TPGS)
  • TPGS stabilizer polyethylene glycol vitamin E succinic acid
  • step 3 Mix the prepared camptothecin nanocrystal suspension in step 1 with the blank gel prepared in step 2, and stir the magnetic bath uniformly to obtain the camptothecin nanocrystalline gel composition.
  • the vortex was 10 min, the vortex speed was 2400 rpm, and then it was ultrasonicated at 100 W for 10 min in a KQ-100DE ultrasonic cleaner to obtain a uniform transparent Itrakang.
  • the middle vortex was 10 min, the vortex speed was 2400 rpm, and then the ultrasonic suspension was immersed in a KQ-100DE ultrasonic cleaner at 100 W for 15 min to obtain a suspension of dexamethasone nanocrystals.
  • the equipment factory was vortexed for 10 min, and the vortex speed was 2,400 rpm. Then, it was ultrasonicated at 100 W for 10 min in a KQ-100DE ultrasonic cleaner to obtain a suspension of cortisone acetate nanocrystals.
  • NCs-Gel drug nanocrystalline gel composition
  • Example 1 2 ml of the drug nanocrystalline gel composition (NCs-Gel) prepared in Example 1 was weighed and added to a flat bottom vial (2.2 cm in diameter), and preheated to 37 ° C in a water bath to form a semi-solid gel. 8 mL of the release medium (0.9% NaCl solution) preheated to 37 °C was carefully added to the gel surface. The vial was then placed in a 37 ° C gas bath thermostat (ZHWY-100C, Shanghai Zhicheng Analytical Instrument) and shaken at 40 rpm.
  • ZHWY-100C Shanghai Zhicheng Analytical Instrument
  • the release results are shown in the release graph of Figure 2.
  • the cumulative release amount of the pharmaceutical nanocrystal gel composition prepared in the present application at 37 ° C for 35 days is less than 80%. Therefore, the pharmaceutical nanogel composition of the present application can significantly delay the release time of the drug, thereby prolonging the action time of the drug and providing a therapeutic effect.
  • the suspension of the drug nanocrystals prepared in Example 1 was stored at 4 ° C and room temperature for 14 days, respectively, and the pharmaceutical nanocrystal gel composition prepared in Example 1 was stored at room temperature for 3 months.
  • the particle size was measured at 0 days, 1 day, 3 days, 7 days, 10 days, 14 days, 1 month, and 3 months, respectively.
  • the particle diameter measuring instrument was a Malvern laser particle size analyzer (Malvem, Zetasizer Nano, UK).
  • the determination method is as follows: firstly, the drug nanocrystal suspension and the drug nanocrystal gel composition are diluted 10 times and 100 times with purified water, and 1.2 ml is added to the sample pool, low-power ultrasound (ultrasound KQ-100DE, Kunshan Ultrasonic Instruments, power 80%) 2-3min, particle size. Repeat the average of 3 times.
  • mice Female BALB/c mice (18-22g, Beijing Weitong Lihua experimental animals) were inoculated with 106 mouse breast cancer 4T1 cells under the right sac, and administered for 13 days after inoculation.
  • the components were divided into 6 groups, respectively : saline group (Saline), blank gel group (Blank F127-Gel, prepared according to the method described in Example 1, except that the blank gel does not contain paclitaxel), paclitaxel (PTX) nanocrystalline gel composition ( Prepared according to the method of Example 1, NCs-Gel), paclitaxel complex micelle gel (MMG, prepared according to the following literature method: Yang Y, J Control Release, 2009, 135, 175-182), paclitaxel nanocrystals (NCs) (The suspension of paclitaxel nanocrystal prepared according to Example 1, using purified water as a solvent during use), paclitaxel injection (Taolol, Bristol-Myers Squibb, lot number: OM43146
  • mice The body weight of the mice was measured every 2 days after administration, and the signs and behaviors of the mice were observed.
  • V [length X (width) 2 ]/2) was calculated.
  • Draw a tumor volume-time change plot The animals were sacrificed on the 20th day after the administration, the tumor was exfoliated, the tumor weight was weighed, and the tumor was photographed.
  • Example 19 Antitumor efficacy of a mouse loaded with MCF-7 tumor after intratumoral administration of a poorly soluble drug nanocrystalline gel composition
  • mice Female BALB/c mice (20-22 g, Beijing Weitong Lihua experimental animals) were inoculated with 106 human breast cancer MCF-7 cells under the right iliac crest. After 14 days of inoculation, the drug-administered components were divided into 5 groups.
  • saline group (Saline), blank gel group (Blank F127-Gel, prepared according to the method described in Example 1, except that the blank gel does not contain paclitaxel), paclitaxel (PTX) nanocrystals
  • Gel composition prepared according to the method of Example 1, NCs-Gel
  • paclitaxel complex micelle gel MMG, prepared according to the following literature method: Yang Y, J Control Release, 2009, 135, 175-182)
  • NCs Paclitaxel nanocrystals
  • NCs Paclitaxel nanocrystals
  • paclitaxel injection (Taxol, Bristol-Myers Squibb, lot number: OM43146)
  • dose For 30 mg PTX/kg, 6 rats in each group, single dose.
  • Tumor body weight was measured every 2 days after administration, and the signs and behaviors of the mice were observed.
  • the animals were sacrificed on the 20th day after the administration, the tumor was exfoliated, the tumor weight was weighed, and the tumor was photographed.
  • NCs-Gel significantly reduces tumor volume with significant differences.
  • the body weight was significantly reduced 2 days after administration, indicating that the Taxol had a certain toxicity after administration.
  • the other drug-administered groups had little effect on body weight, indicating that the systemic toxicity caused by in situ injection was small.
  • the NCs-Gel which has the least influence on the body weight indicates that the NCs-Gel of the present application has a remarkable effect and a small side effect.
  • the present invention is merely an exemplary embodiment 1 as an experimental drug, and it is to be noted that other embodiments of the present invention have the same or similar advantageous effects.
  • the poorly soluble pharmaceutical gel composition provided by the present application can improve the drug loading amount of the poorly soluble drug, avoid the problem of drug deposition occurring during long-term storage, improve the needle-forming property of the injection, and improve the uniform distribution and release of the drug. Sex, etc., has important practical significance.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • General Health & Medical Sciences (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Dermatology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Inorganic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne une composition de gel de médicament insoluble comprenant un nanocristal médicamenteux de médicament insoluble, un stabilisateur, une substance thermosensible et un solvant. La composition de gel de médicament insoluble pourrait augmenter la charge médicamenteuse du médicament insoluble, éviter le dépôt du médicament pendant une conservation à long terme, améliorer l'aptitude de passage par une aiguille d'une injection et améliorer l'uniformité du médicament et sa libération.
PCT/CN2014/070369 2013-01-10 2014-01-09 Composition de gel de médicament insoluble et son procédé de préparation WO2014108076A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201310009133.0 2013-01-10
CN201310009133.0A CN103054794B (zh) 2013-01-10 2013-01-10 难溶性药物凝胶组合物及其制备方法

Publications (1)

Publication Number Publication Date
WO2014108076A1 true WO2014108076A1 (fr) 2014-07-17

Family

ID=48097897

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2014/070369 WO2014108076A1 (fr) 2013-01-10 2014-01-09 Composition de gel de médicament insoluble et son procédé de préparation

Country Status (2)

Country Link
CN (1) CN103054794B (fr)
WO (1) WO2014108076A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2544843B (en) * 2015-07-14 2022-08-03 Professional Compounding Centers Of America Pcca Poloxamer-based intralesional injections for the delivery of chemotherapeutic agents

Families Citing this family (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103054794B (zh) * 2013-01-10 2016-05-25 北京大学 难溶性药物凝胶组合物及其制备方法
CN104224688B (zh) * 2013-06-09 2017-10-10 北京化工大学 负载纳米药物的丙烯酸酯化透明质酸水凝胶及其制备方法
CN103768046B (zh) * 2014-02-21 2018-06-05 中国人民解放军军事医学科学院毒物药物研究所 一种注射用紫杉醇纳米晶体及其制备方法
CN104288091B (zh) * 2014-05-30 2017-04-19 河南科技大学 一种利培酮纳米混悬温敏凝胶剂及其制备方法
CN104688721A (zh) * 2014-10-11 2015-06-10 黄萍 一种含紫杉醇脂质体的抗类风湿性关节炎药物凝胶剂及其制备方法
CN104296988B (zh) * 2014-10-31 2018-04-06 江西江钨浩运科技有限公司 一种激光粒度校验标准筛的方法
CN104622794B (zh) * 2015-01-16 2018-04-06 北京大学 一种联合分子靶向药物和细胞毒药物的凝胶注射剂
CN106994117B (zh) * 2016-01-25 2020-05-05 上海市肿瘤研究所 一种治疗胆系肿瘤的药物纳米复合温敏凝胶剂
CN105688184B (zh) * 2016-03-11 2018-03-20 杜峰 一种用于治疗骨肉瘤的皮下注射用原位凝胶
CN108653236A (zh) * 2017-03-31 2018-10-16 复旦大学 一种生物膜包载药物纳米晶体的制备方法及其用途
CN108245662A (zh) * 2017-07-10 2018-07-06 上海昊海生物科技股份有限公司 一种温敏型环孢素眼用水凝胶及其制备方法
CN109331184A (zh) * 2017-08-01 2019-02-15 复旦大学 一种荷正电药物纳米结晶制剂及其制备方法
CN108836947A (zh) * 2018-07-12 2018-11-20 天津双硕医药科技有限公司 一种维奈妥拉纳米晶体口服固体药物组合物
CN109316441B (zh) * 2018-10-31 2021-04-23 成都医学院 一种布地奈德直肠原位温敏凝胶及其制备方法和用途
CN109893501A (zh) * 2019-03-26 2019-06-18 齐鲁工业大学 一种水飞蓟宾纳米笼式纳米晶注射液的制备方法
CN111202710B (zh) * 2019-12-17 2022-03-25 中国药科大学 一种氯硝柳胺纳晶温敏凝胶及其制备方法、应用
CN111039821B (zh) * 2019-12-17 2022-03-11 中国药科大学 一种磷酸盐稳定氯硝柳胺纳晶及其制备方法和应用
CN112402363A (zh) * 2020-10-15 2021-02-26 福建中医药大学 石杉碱甲二元醇质体温敏凝胶鼻腔给药制剂及制备方法
CN112641950B (zh) * 2021-01-12 2022-12-16 北京德立福瑞医药科技有限公司 含有难溶性抗肿瘤活性剂的药物组合物及其制备方法
CN113520992A (zh) * 2021-07-27 2021-10-22 陈芹 一种川芎嗪纳米晶体、川芎嗪纳米晶体温敏性水凝胶、制备方法及其应用
CN115192530A (zh) * 2022-07-14 2022-10-18 深圳大学 二萜内酯化合物及其制备方法

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101322682A (zh) * 2008-07-29 2008-12-17 沈阳药大制剂新技术有限公司 难溶性药物纳米粒的制备方法
CN101342142A (zh) * 2008-07-24 2009-01-14 北京大学 一种可注射的温敏原位凝胶制剂,它们的制备方法及其应用
CN102349871A (zh) * 2011-10-20 2012-02-15 中国科学院过程工程研究所 一种10-羟基喜树碱的纳微给药体系及其制备方法
CN102525882A (zh) * 2012-02-28 2012-07-04 上海市肿瘤研究所 一种纳米复合温敏凝胶剂及其制备方法和应用
CN103054794A (zh) * 2013-01-10 2013-04-24 北京大学 难溶性药物凝胶组合物及其制备方法

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101342142A (zh) * 2008-07-24 2009-01-14 北京大学 一种可注射的温敏原位凝胶制剂,它们的制备方法及其应用
CN101322682A (zh) * 2008-07-29 2008-12-17 沈阳药大制剂新技术有限公司 难溶性药物纳米粒的制备方法
CN102349871A (zh) * 2011-10-20 2012-02-15 中国科学院过程工程研究所 一种10-羟基喜树碱的纳微给药体系及其制备方法
CN102525882A (zh) * 2012-02-28 2012-07-04 上海市肿瘤研究所 一种纳米复合温敏凝胶剂及其制备方法和应用
CN103054794A (zh) * 2013-01-10 2013-04-24 北京大学 难溶性药物凝胶组合物及其制备方法

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
GUPTA, S. ET AL.: "Dual-Drug Delivery System Based on In SituGel-Forming Nanosuspension of Forskolin to Enhance Antiglaucoma Efficacy.", AAPS PHARMSCITECH, vol. 11, no. 1, March 2010 (2010-03-01), pages 322 - 335 *
LIU, FENG ET AL.: "Sustained-release progesterone nanosuspension following intramuscular injection in ovariectomized rats", INTERNATIONAL JOURNAL OF NANOMEDICINE, vol. 5, 10 November 2010 (2010-11-10), pages 943 - 954 *
LIU, FENG ET AL.: "Targeted Cancer Therapy With Novel High Drug-Loading Nanocrystals", JOURNAL OF PHARMACEUTICAL SCIENCES, vol. 99, no. 8, 5 April 2010 (2010-04-05), pages 3542 - 3551 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2544843B (en) * 2015-07-14 2022-08-03 Professional Compounding Centers Of America Pcca Poloxamer-based intralesional injections for the delivery of chemotherapeutic agents

Also Published As

Publication number Publication date
CN103054794A (zh) 2013-04-24
CN103054794B (zh) 2016-05-25

Similar Documents

Publication Publication Date Title
WO2014108076A1 (fr) Composition de gel de médicament insoluble et son procédé de préparation
Mohammad et al. Drug nanocrystals: Fabrication methods and promising therapeutic applications
Liu et al. A thermo-responsive and self-healing liposome-in-hydrogel system as an antitubercular drug carrier for localized bone tuberculosis therapy
Zhu et al. Co-delivery of chemotherapeutic drugs with vitamin E TPGS by porous PLGA nanoparticles for enhanced chemotherapy against multi-drug resistance
Fang et al. Nanostructured lipid carriers (NLCs) for drug delivery and targeting
Kalaria et al. Design of biodegradable nanoparticles for oral delivery of doxorubicin: in vivo pharmacokinetics and toxicity studies in rats
Tekade et al. Solid lipid nanoparticles for targeting and delivery of drugs and genes
Wang et al. Controlled preparation and antitumor efficacy of vitamin E TPGS-functionalized PLGA nanoparticles for delivery of paclitaxel
ES2685743T3 (es) Procedimiento para la fabricación de nanopartículas cargadas con principio activo
Sheu et al. Codelivery of doxorubicin-containing thermosensitive hydrogels incorporated with docetaxel-loaded mixed micelles enhances local cancer therapy
ES2737955T3 (es) Complejos de acetato de abiraterona, proceso para la preparación de los mismos y composiciones farmacéuticas que los contienen
Lin et al. A novel oral delivery system consisting in “drug-in cyclodextrin-in nanostructured lipid carriers” for poorly water-soluble drug: Vinpocetine
PT1392254E (pt) Sistemas de distribuição micelares de fármacos para fármacos hidrofóbicos.
Danhier et al. Nanosuspension for the delivery of a poorly soluble anti-cancer kinase inhibitor
Fan et al. Nanocrystal technology as a strategy to improve drug bioavailability and antitumor efficacy for the cancer treatment
Wang et al. Enhanced encapsulation and bioavailability of breviscapine in PLGA microparticles by nanocrystal and water-soluble polymer template techniques
TWI745358B (zh) 含有細微粒子之組合物及其製法
CN105232459A (zh) 一种复溶自组装的水难溶性药物聚合物胶束组合物及其制备方法
US11931456B2 (en) Pharmaceutical compositions containing mixed polymeric micelles
Manjappa et al. Is an alternative drug delivery system needed for docetaxel? The role of controlling epimerization in formulations and beyond
Han et al. A new approach to produce drug nanosuspensions CO2-assisted effervescence to produce drug nanosuspensions
Mougin et al. Elongated self-assembled nanocarriers: From molecular organization to therapeutic applications
US20080171687A1 (en) Compositions And Methods For The Preparation And Administration Of Poorly Water Soluble Drugs
Waheed et al. Lyotropic liquid crystalline nanoparticles: Scaffolds for delivery of myriad therapeutics and diagnostics
Chao et al. Nanotechnology-based drug delivery systems for the improved sensitization of tamoxifen

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 14737988

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 14737988

Country of ref document: EP

Kind code of ref document: A1