WO2006066500A1 - Procédé de synthèse de dérivés de quinazoline et application à la fabrication d'un médicament pour le traitement d'une maladie de type tumoral - Google Patents

Procédé de synthèse de dérivés de quinazoline et application à la fabrication d'un médicament pour le traitement d'une maladie de type tumoral Download PDF

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Publication number
WO2006066500A1
WO2006066500A1 PCT/CN2005/002253 CN2005002253W WO2006066500A1 WO 2006066500 A1 WO2006066500 A1 WO 2006066500A1 CN 2005002253 W CN2005002253 W CN 2005002253W WO 2006066500 A1 WO2006066500 A1 WO 2006066500A1
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Prior art keywords
nasal
delivery system
drug
trehalose
drug delivery
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PCT/CN2005/002253
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English (en)
Chinese (zh)
Inventor
Peixue Ling
Xiaohua Rong
Lijun Hou
Tianmin Zhang
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Peixue Ling
Xiaohua Rong
Lijun Hou
Tianmin Zhang
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Application filed by Peixue Ling, Xiaohua Rong, Lijun Hou, Tianmin Zhang filed Critical Peixue Ling
Publication of WO2006066500A1 publication Critical patent/WO2006066500A1/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
    • A61K9/0043—Nose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • 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

Definitions

  • the present invention relates to a nasal drug delivery system and a method of preparing the same, and more particularly, to a nasal drug delivery system of the present invention comprising a pharmaceutically acceptable salt of a hyaluronic acid and/or a hyaluronic acid and a conventional pharmaceutical excipient which is acceptable for nasal administration.
  • the ideal nasal drug delivery system should have the following characteristics: It can prolong the action time of the drug; It can enhance the absorption of the drug; It can improve the bioavailability of the drug; It can reduce the toxicity of the drug. In particular, systemic toxicity; can extend the stability and shelf life of the drug; improve the adaptability of the nasal cavity to the environment; have good biocompatibility.
  • the main components of the current nasal delivery system are viscous excipients, such as cellulose, polyvinyl alcohol, etc., which only have a viscosity-increasing effect, which only prolongs the action time of the drug in the nose to some extent. . This is a far cry from the ideal nasal delivery system.
  • the nasal drug delivery system of the present invention preferably further comprises one or more pharmacologically active ingredients.
  • the pharmacologically active ingredient is preferably selected from the group consisting of an antimicrobial agent, a non-anti-inflammatory drug, an adrenocortical hormone drug, an antiallergic drug, a vasoconstrictor drug, a local anesthetic drug, a symptom relief drug, a healing promoting drug, and other pharmacologically active ingredients.
  • the antimicrobial drug is an antibiotic drug, preferably selected from the group consisting of chloramphenicol, gentamicin sulfate, lincomycin and rifampicin; or a quinolone drug, preferably selected from norfloxacin, left-handed Ofloxacin, ofloxacin, ciprofloxacin, lomefloxacin, rufloxacin, fleroxacin and pefloxacin; or a sulfonamide, preferably sulfadiazine; or an antiviral, preferably Selected from acyclovir, adenosine and ribavirin; wherein the non-steroidal anti-inflammatory drug is preferably selected from the group consisting of diclofenac sodium, piroxicam and meloxicam; the adrenocortical hormone is preferably selected from the group consisting of dexamethasone phosphate Sodium, dexamethasone acetate, hydrocortisone and beta
  • the pharmacologically active ingredient may be one or a plurality of different types or a plurality of different classes.
  • the composition is trehalose 0.11 to 50 g, glass acid and / Or pharmaceutically acceptable salt of glass acid 0. 01 ⁇ 20 grams, other pharmacological active ingredients 0 ⁇ appropriate amount, appropriate amount of pharmaceutical auxiliary materials.
  • the nasal drug delivery system of the present invention is preferably a solution formulation, a gelling agent, a dispersion formulation, a bone agent or an ointment.
  • the invention also provides a method of the nasal drug delivery system, the method comprising:
  • the medicinal salt of trehalose and hyaluronic acid and/or glass acid is placed in an appropriate amount of water to be dissolved and ready for use;
  • the auxiliary material is dissolved in an appropriate amount. If necessary, other pharmacologically active ingredients are dissolved.
  • the trehalose and the glass acid solution are added, and then the purified ice is added to the volume to obtain trehalose and hyaluronic acid and/or glass acid.
  • a solution preparation or a gelling agent for medicinal salt after sterilization, and dispensing and sealing, thereby obtaining the nasal drug delivery system of the present invention;
  • trehalose and hyaluronic acid and/or pharmaceutically acceptable salt of glass acid and other ingredients are conventional.
  • the preparation of the dispersion preparation or the ointment or the ointment or the like is prepared to obtain a dispersion preparation or a paste or an ointment, and after sterilization, the seal is dispensed to obtain the nasal drug delivery system of the present invention.
  • the present invention also provides the use of trehalose in combination with a pharmaceutically acceptable salt of a glass acid and/or a hyaluronic acid for the preparation of a nasal delivery system for treating dry rhinitis, atrophic rhinitis, allergies Prevention and treatment of various nasal diseases such as rhinitis, hypertrophic rhinitis, nosebleeds, and sinusitis.
  • the present invention also provides the use of a urinary drug delivery system for the treatment of the delivery of other pharmacologically active ingredients in combination with a pharmaceutically acceptable salt of hyaluronic acid and/or a hyaluronic acid for the treatment of dryness.
  • Rhinitis atrophic rhinitis, Allergic rhinitis, hypertrophic rhinitis, nose bleeding, sinusitis and other nasal diseases or systemic diseases;
  • the pharmacologically active ingredients are selected from the group consisting of antimicrobial agents, non-steroidal anti-inflammatory drugs, adrenocortical drugs, anti-allergic reactions Medicines, vasoconstrictors, local anesthetics, symptom relief drugs, healing agents, and other pharmacologically active ingredients.
  • the present invention also provides a method for treating or preventing dry rhinitis, atrophic rhinitis, allergic rhinitis, hypertrophic rhinitis, epistaxis, sinusitis, including administering to a patient having such a need, the nasal drug delivery system of the present invention .
  • the present invention also provides a method for promoting the delivery of a pharmacologically active ingredient in a nasal drug delivery system, the method comprising adding trehalose and a hyaluronic acid and/or a pharmaceutically acceptable salt of a hyaluronic acid to the nasal drug delivery system;
  • the delivery system is for treating various nasal diseases or systemic diseases such as dry rhinitis, atrophic rhinitis, allergic rhinitis, hypertrophic rhinitis, nose bleeding, sinusitis, etc.
  • the pharmacologically active ingredient is selected from the group consisting of an antimicrobial agent, a non- ⁇ Anti-inflammatory drugs, adrenocortical drugs, anti-allergic drugs, vasoconstrictors, local anesthetics, symptom relief drugs, healing agents, and other pharmacologically active ingredients.
  • the main components of the nasal drug delivery system of the present invention are trehalose and hyaluronic acid, and the basic constituents thereof are
  • Trehalose (English: treha lose) is widely distributed throughout the biological world, including bacteria, fungi, insects, other plants and animals, which have special protective effects on biomolecules:
  • Trehalose is a disaccharide that plays a key role in dehydration, enabling many organisms to remain under abnormal conditions such as high temperature, dehydration, freezing, and drying.
  • the original activity can fundamentally improve the cell's own anti-drying and anti-freezing ability.
  • Trehalose can protect the biofilm by lowering the phase transition temperature and keeping the membrane lipid under dehydration conditions in a liquid crystal state. Protection of biomolecules such as proteins: Trehalose has a significant protective effect on dehydrated and dried living substances. Even in extremely dry environments, it can stabilize biomolecules such as proteins without damage.
  • Trehalose has been widely used as a formulation stabilizer and preservative, which is unmatched by other carbohydrates.
  • trehalose can enter the cell and directly act on the cell, exert its unique water substitution stress factor, improve the anti-drying and anti-freezing ability of the cell, thereby improving the ability of the cell to adapt to the environment;
  • Membrane, protein and other biomolecules and nasal tissue stability reduce the toxicity and systemic toxicity of the drug on normal tissues of the nasal cavity; can be used as a stabilizer and preservative for the preparation to enhance the stability of the drug and prolong the shelf life of the preparation; Biocompatibility, etc.
  • Glass acid (English: hya luronic ac id, also known as hyaluronic acid) is naturally present in humans, and its glassy acid is present and applied in the form of its sodium salt, sodium hyaluronate (English: sodium hya lurona te).
  • the glass acid of the present invention includes a salt of glass acid, that is, a pharmaceutically acceptable salt of sodium hyaluronate or other hyaluronic acid, which has unique viscoelastic and non-Newtonian fluid properties, and has important pharmacological and physiological functions. :
  • Glass acid is called the ideal natural moisturizing factor. Its carboxyl group and other polar groups in the molecule can form hydrogen bonds with water to bind a large amount of water. Moreover, the glass acid can automatically adjust the water absorption according to the humidity of the environment. This intelligent moisturization keeps the nasal cavity in optimal humidity at all times.
  • the glass acid solution has good viscoelasticity. At low impact frequency, ie low shear rate, the solution is viscous and can reduce the friction between tissues. At high impact frequency, ie high shear rate, the solution is elastic. Tissue damage can be avoided.
  • Vitreic acid is an indispensable substance in wound-free scar repair, which can inhibit inflammation and repair nasal mucosal damage.
  • Viscosity enhancement The bioavailability of the drug is positively correlated with the viscosity of the drug solution within a certain range. Maintaining the proper viscosity is an important prerequisite for the drug to play an effective role. As a natural biomacromolecular polysaccharide, hyaluronic acid can increase the viscosity of the liquid.
  • Bioadhesiveness Compared with other high molecular polymers, glass acid has the same viscosity or even lower viscosity, which enables the drug to achieve higher bioavailability, thus delaying the elimination of drugs, which mainly depends on the acid of glass acid. Adhesion.
  • Vitreic acid has the effect of slow release of the drug and is determined by its molecular specificity.
  • the drug can be embedded in the macromolecular network of hyaluronic acid by non-covalent bonding.
  • the hyaluronic acid molecule acts like a dynamic molecular sieve, and the drug adheres to the surface of the nasal cavity for a long time.
  • Non-Newtonian fluid characteristics Although synthetic polymer and other substances can increase the viscosity of the liquid, prolong the residence time of the liquid in the nasal mucosa and improve the therapeutic effect, however, the synthetic polymer solution used is basically Newtonian fluid, when the viscosity increases. To a certain extent, it will make the inside of the nasal cavity feel sticky and uncomfortable.
  • the glass acid solution is a non-Newtonian fluid with unique viscoelasticity, and the viscosity is rapidly lowered at a high shear rate, which overcomes the deficiency of a tackifier such as a synthetic polymer.
  • Glass acid can act on the intercellular space and connective tissue, improve the functions of hydration, moisturizing, lubrication, etc., improve the living environment of cells; through its adhesion, bioadhesion and sustained release, and the characteristics of non-Newtonian fluids. And good biocompatibility, prolong the retention time of the drug on the surface of the nasal cavity, improve the bioavailability of the drug, reduce the side effects of the drug, and reduce the irritation of the drug solution.
  • the nasal drug delivery system of the invention can be directly used for the prevention and treatment of dry rhinitis and nasal cavity cleaning, and can also be added with pharmacologically active ingredients for the delivery of pharmacologically active ingredients, for dry rhinitis, atrophic rhinitis, allergic rhinitis, hypertrophy Prevention of various nasal diseases or systemic diseases such as rhinitis, nosebleeds, and sinusitis.
  • pharmacologically active ingredients include anti-microbial drugs, non-anti-inflammatory drugs, adrenocortical drugs, and anti-drugs. Allergic drugs, vasoconstrictors, local anesthetics, symptom relief drugs, promoting healing or other pharmacologically active ingredients.
  • antibiotics such as chloramphenicol, gentamicin, neomycin sulfate, lincomycin, rifampicin in antimicrobials; quinolones such as norfloxacin in antimicrobials Star, levofloxacin, ofloxacin, ciprofloxacin, enoxacin, lomefloxacin, rufloxacin, fleroxacin, pefloxacin, etc.; sulfa drugs such as sulfadiazine in antimicrobials; Antiviral drugs in antimicrobial drugs such as acyclovir, adenosine, ribavirin, etc.; non-steroidal anti-inflammatory drugs such as diclofenac sodium, piroxicam, meloxicam, etc; adrenal corticosteroids such as Dexamethasone sodium phosphate, dexamethasone acetate, hydrocortisone, betamethasone sodium phosphate, etc.; antiallergic
  • the trehalose of the present invention refers to trehalose of any origin, which is obtained by extracting and separating from plants, animal tissues, microbial fermentation, and genetic engineering preparation, and the like.
  • the trehalose of the present invention means trehalose in any form, including trehalose containing no crystal water and trehalose containing crystal water, and the like.
  • the glass acid of the present invention refers to a glass acid of any source, which is obtained by extracting and separating from animal tissues, microbial fermentation, and genetic engineering preparation, and the like.
  • the glass acid of the present invention includes glass acid and salts thereof such as sodium hyaluronate (also known as sodium hyaluronate), zinc hyaluronate (also known as zinc hyaluronate), and the like.
  • the glass acid of the present invention refers to any glass acid of a relative molecular mass. Unless specified otherwise, the glass acids described herein include glass acids and/or pharmaceutically acceptable salts thereof.
  • the nasal drug delivery system of the present invention can be made into various dosage forms suitable for nasal administration, including liquid preparations, such as solut ions, suspensions, emulsions, and emulsions.
  • liquid preparations such as solut ions, suspensions, emulsions, and emulsions.
  • the nasal drug delivery system of the present invention When the nasal drug delivery system of the present invention is formulated into a solution, the usual solvents are: water, glycerin, liquid paraffin, vegetable oil, and the like. When the nasal drug delivery system of the present invention is formulated as a suspension, the usual suspensions are Tween, Span, and the like. When the nasal drug delivery system of the present invention is formulated into an emulsion, the usual substrates are: lanolin, fatty alcohol, polysorbate, sodium soap, triethanolamine soap, and the like.
  • the nasal drug delivery system of the present invention When the nasal drug delivery system of the present invention is formulated into a gelling agent, commonly used gel aqueous substrates are: glycerin, propylene glycol, cellulose ether compounds, carbomer, gelatin, etc.; commonly used gel oily substrates are: liquid paraffin , fatty oil, aluminum soap, etc.
  • the nasal drug delivery system of the present invention When the nasal drug delivery system of the present invention is formulated into a paste, the commonly used substrates are: vegetable oil, red dan, official powder, and the like.
  • the nasal drug delivery system of the present invention When the nasal drug delivery system of the present invention is formulated into an ointment, the usual substrates are: polyethylene glycol, petrolatum, paraffin, liquid paraffin, silicone oil, beeswax, stearic acid and the like.
  • the nasal delivery system of the present invention When the nasal delivery system of the present invention is formulated into a milk bone, the commonly used substrates are: petrolatum,
  • the nasal drug delivery system of the present invention may further comprise a conventional pH adjusting agent to adjust the pH of the nasal drug delivery system to a pH range acceptable for conventional nasal administration, preferably a pH of 4-9, more preferably a pH of 5-8. Most preferably the pH is from 6.5 to 7.5.
  • a conventional pH adjusting agent may be a pharmaceutically acceptable organic or inorganic acid or base, preferably sodium hydroxide, hydrochloric acid, boric acid, borax, a phosphate-phosphate buffer system, a boric acid-borax buffer system, an acetate-acetate buffer. System and so on.
  • the osmotic pressure regulating agent may also be added to the nasal drug delivery system of the present invention, for example, preferably any combination of one or more of the following: sodium chloride, low molecular weight dextran, glycerin, boric acid, borax, phosphoric acid - Phosphate buffer system, boric acid-borax buffer system and acetic acid-acetate buffer system can be used as pH adjuster, As an osmotic pressure regulator.
  • preservatives such as hydroxyphenylethyl ester, thimerosal, EDTA and the like may also be added to the nasal delivery system of the present invention.
  • the preparation method of the nasal drug delivery system of the present invention is: if all the components in the formulation are soluble in water, preferably, the formulation and amount of the nasal drug delivery system according to the present invention, trehalose and hyaluronic acid and/or The pharmaceutically acceptable salt of hyaluronic acid is put into an appropriate amount of water, and it is dissolved and used for later; the appropriate amount of the auxiliary agent is dissolved, and if necessary, other pharmacologically active ingredients are dissolved, and after the solution is cooled, trehalose and a glass acid solution are added, and then purified.
  • a dosage form containing a solution or a gel containing trehalose and hyaluronic acid is obtained, and after filtration sterilization or dry heat sterilization or moist heat sterilization or chemical sterilization, the seal is dispensed to obtain the nasal drug delivery system of the present invention.
  • the preparation method of the nasal drug delivery system of the present invention may further be: if the formulation has water-insoluble components, or all components are soluble in water, according to the formulation and dosage of the nasal drug delivery system of the present invention, trehalose and hyaluronic acid and/or
  • the pharmaceutically acceptable salt of the glass acid and other ingredients are prepared by a conventional method for preparing a dispersion preparation or a paste or an ointment to obtain a dispersion preparation (including a liposome solution, a micelle solution, a microemulsion, etc.) or a paste or ointment.
  • the dosage form such as the agent, the filter sterilization or dry heat sterilization or the moist heat sterilization or the chemical sterilization, and the sealing after the dispensing, the nasal drug delivery system of the invention is obtained.
  • the nasal drug delivery system containing trehalose and hyaluronic acid has the following significant advantages: 1 Trehalose can enter the cell and directly act on the cell, exert its unique water substitution stress factor, and improve the cell's anti-drying and anti-freezing ability. Thereby improving the ability of cells to adapt to the environment; maintaining biofilms such as biofilms, protein shields and nasal mucosa, reducing the toxicity and systemic toxicity of drugs on normal tissues of the nasal cavity; as a preservative for preparations and as a preservative for products, The shelf life of the formulation is extended; it has good biocompatibility and the like.
  • 2Glass acid can act on the intercellular space and connective tissue, improve the functions of hydration, moisturizing, lubrication, etc., and improve the living environment of cells; Adhesion, bioadhesion, spread wetting and sustained release, non-Newtonian fluid properties and good biocompatibility, prolong the residence time of the drug in the nasal cavity, improve the bioavailability of the drug, reduce the toxic side effects of the drug, reduce the drug solution Irritating, improving the comfort of the nose drops, etc. 3
  • the combination of trehalose and hyaluronic acid protects and improves the cells from the inside to the outside, improves the ability of cells to adapt to harsh environments, and improves the living environment of cells, thereby complementing each other and increasing each other.
  • the molecular structure of trehalose is as follows
  • trehalose The molecule of trehalose is formed by the condensation of two glucose molecules through a hemiacetal hydroxyl group. Trehalose has many forms of existence, the most common being dihydrate crystals, which lose their knots. Crystal water turns into anhydrous crystals. Regardless of the form of trehalose, its physicochemical properties are stable and chemically inert.
  • the molecular structure of hyaluronic acid is as follows.
  • the hyaluronic acid is a linear mucopolysaccharide composed of glucose butyric acid and acetyl glucosamine as disaccharide units.
  • the nasal drug delivery system of the present invention in 100 ml, trehalose 1. 5 g, sodium hyaluronate Q. 10 g, sodium chloride Q. 70 g, borax Q. 05 g, the rest is purified water, prepared into a solution .
  • the nasal delivery system of the present invention in 100 ml, trehalose 1.5 , sodium hyaluronate 0. 10, chloramphenicol 0. 25 g, sodium chloride 0. 68 g, borax Q. 0 5 g, hydroxybenzene Ethyl ester 0. 03 g, the rest is purified water, prepared as a solution.
  • Example 4 The nasal drug delivery system of the invention is, in 100 ml, 1.5 g of trehalose, 0.10 g of sodium hyaluronate, Q.3 g of levofloxacin, 0.60 g of sodium chloride, 0.05 g of borax, 0.03 g of hydroxyphenyl ester, and the rest is purified water. , prepared as a solution.
  • the nasal drug delivery system of the present invention in 100 ml, 1.0 g of trehalose, 0.10 g of sodium hyaluronate, 0.01 g of acyclovir, 0.75 g of sodium chloride, 0.05 g of borax, 0.03 g of hydroxyphenyl ester, and the others are purified. Water, prepared as a solution.
  • the nasal drug delivery system of the present invention is, in 100 ml, 2.0 g of trehalose, 0.20 g of sodium hyaluronate, 0.1 g of diclofenac sodium, 0.65 g of sodium chloride, 0.05 g of borax, 0.03 g of hydroxyphenylethyl ester, and the rest is purified water. Prepared as a solution.
  • the nasal drug delivery system of the present invention is 100 liters, 1.5 g of trehalose, 0.15 g of sodium hyaluronate, 0.1 g of dexamethasone sodium phosphate, 0.72 g of sodium chloride, 0.05 g of borax, 0.03 g of hydroxyphenyl ester, and the rest. To purify the water, a solution is prepared.
  • the nasal drug delivery system of the invention is, in 100 ml, 1.0 g of trehalose, 0.20 g of sodium hyaluronate, 1.2 g of sodium cromoglycate, 0.70 g of sodium chloride, 0.05 g of borax, 0.03 g of hydroxyphenylethyl ester, and the rest is purified water. , prepared as a solution.
  • the nasal drug delivery system of the present invention in 100 liters, 1.0 g of trehalose, 0.10 g of sodium hyaluronate, 0.02 g of norepinephrine, 0.75 g of sodium chloride, 0.05 g of borax, 0.05 g of vitamin E acetate, hydroxybenzene Ethyl ester 0.03 g, the remainder being purified water, prepared as a solution.
  • the nasal drug delivery system of the present invention in 100 ml, trehalose 2.0 g, 0.15 g of sodium hyaluronate, Q.4 g of zinc sulfate, 0.62 g of sodium chloride, 0.05 g of borax, 0.03 g of hydroxyphenylethyl ester, and the rest were purified water, and prepared into a solution.
  • the nasal drug delivery system of the present invention in 100 ml, 1.5 g of trehalose, 0.10 g of sodium hyaluronate, G.25 g of tropicamide, Q.68 g of sodium chloride, 0.05 g of borax, 0.03 g of hydroxyphenyl ester
  • the rest is purified water and prepared as a solution.
  • the nasal drug delivery system of the present invention is 100 liters, 1.0 g of trehalose, 0.10 g of sodium hyaluronate, 3 g of chondroitin sulfate, 0.72 g of sodium chloride, 0.05 g of borax, 0.03 g of hydroxyphenyl ester, and the others are purified. Water, prepared as a solution.
  • the nasal drug delivery system of the present invention in 100 ml, 1.0 g of trehalose, 0.10 g of sodium hyaluronate, 1.5 g of dextromethorphan hydrobromide, 0.72 g of sodium chloride, 0.05 g of borax, 0.03 g of hydroxyphenylethyl ester, the rest To purify the water, a solution is prepared.
  • the nasal drug delivery system of the present invention in 100 g, trehalose 1.5 g, sodium hyaluronate 1.0 g, lysozyme 1 g, glycerol 2.3 g, hydroxyphenylethyl ester 0.03 g, the rest is purified water, prepared into aqueous coagulum Glue.
  • the nasal drug delivery system of the present invention in 100 g, 1.5 g of trehalose, 0.1 g of sodium hyaluronate, 0.5 g of hydrocortisone acetate, 2.4 g of glycerin, 0.03 g of hydroxyphenylethyl ester, and the rest is purified water, prepared into a mixture Suspending agent.
  • Test Example 1
  • control group 1 the traditional 1.5% dextromethorphan hydrobromide nasal drops
  • control group 2 the traditional 1.5% hydrobromic acid containing 0.1% sodium hyaluronate.
  • Methadine nasal drops control group 2
  • present invention group 13 group The healthy subjects measured the peak concentration of the drug in the blood after dropping 2 mL of the above nasal drops according to randomization.
  • Example 3 of the present invention A sample of Example 3 of the present invention and a chloramphenicol nasal drop containing no trehalose and hyaluronic acid was taken at a temperature of (40 ⁇ 2). C, relative humidity is 20 % ⁇ 2 % The environment was placed for 6 months, and the content of chloramphenicol and its degradation product diol was sampled at 0 1 2 3 4 5 June. The percentage of chloramphenicol in the labeled amount and the diol content in chloramphenicol were calculated. Percentage, the effect of chloramphenicol on the stability of chloramphenicol and the stability of trehalose and hyaluronic acid on chloramphenicol.
  • Example 3 of the present invention Take the sample of Example 3 of the present invention and the chloramphenicol nasal drop containing no trehalose and hyaluronic acid, and place it in an environment with a temperature of (25 ⁇ 2 ) C and a relative humidity of 60 % ⁇ 2%.
  • samples were taken at 0 1 2 3 4 5 6 7 8 9 10 11 12 1 3 14 15 16 17 17 months to determine the content of chloramphenicol and its degradation product diol, and calculate the percentage of chloramphenicol in the labeled amount. And the percentage of diols to chloramphenicol, the stability of chloramphenicol and the effect of trehalose and hyaluronic acid on the stability of chloramphenicol.
  • Chloramphenicol accounts for the degradation product diols as a percentage of chloramphenicol as a percentage of the degradation product diol. Percentage of chloramphenicol as a percentage of chloramphenicol
  • Example 3 of the present invention can significantly reduce the degradation of chloramphenicol.
  • Traditional chlorinated nasal drops are usually valid for 1 year, and chloramphenicol nasal drops containing trehalose and sodium hyaluronate can be used for one and a half years or longer.
  • Example 2 of the present invention The effect of the preparation of Example 2 of the present invention on dry rhinitis was examined by using a commercially available compound mint nasal drop and physiological saline as a control. The patient has 2 drops at a time. After 4 times, the effect was evaluated after 2 weeks of treatment.
  • Cure Nasal dry ventilation improved, normal sense of smell, nasal mucosa returned to normal; improved: Significant improvement in symptoms; Ineffective: No significant improvement in symptoms.
  • Example 2 50 62 36 2 It can be seen from Table 4 that the combination of trehalose and hyaluronic acid in the nasal drug delivery system can significantly improve the symptoms of dry rhinitis, and the effective rate (cure rate + improvement rate) is 98%; Better than ordinary commercial mint nasal drops and normal saline.

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Abstract

La présente invention décrit des dérivés de quinazoline de formule (`), ainsi que leur procédé de synthèse et leur application en tant que médicaments permettant d'inhiber la croissance de tumeurs. Les groupements X, Y, Z, R1, R2, R3, R4 du composé (`) sont tels que définis dans la description de l'invention. Les composés de l'invention peuvent en particulier inhiber l'activité de la tyrosine kinase, ajuster la sécrétion de FCEV, ceci afin de traiter les tumeurs malignes.
PCT/CN2005/002253 2004-12-20 2005-12-20 Procédé de synthèse de dérivés de quinazoline et application à la fabrication d'un médicament pour le traitement d'une maladie de type tumoral WO2006066500A1 (fr)

Applications Claiming Priority (2)

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CNB2004100755489A CN1285382C (zh) 2004-12-20 2004-12-20 含海藻糖和玻璃酸的鼻腔用药传递系统及其制备方法
CN200410075548.9 2004-12-20

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013041696A1 (fr) * 2011-09-21 2013-03-28 F. Holzer Gmbh Spray nasal et gouttes nasales ayant un effet stimulant et tonifiant
CN112006987A (zh) * 2019-12-13 2020-12-01 吉林省健敷鼻科技有限公司 一种治疗鼻炎的冷敷凝胶及其之制备方法
IT202100021659A1 (it) * 2021-08-10 2023-02-10 A&R Pharma Srl Composizione topica e suo uso per il trattamento nasale della rinite

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1302813C (zh) * 2004-12-29 2007-03-07 中国海洋大学 含海藻糖和透明质酸的烧伤用药传递系统及其制备方法
CN102579478A (zh) * 2012-03-30 2012-07-18 济南康众医药科技开发有限公司 玻璃酸钠在制备药物中的应用
CN104147603A (zh) * 2014-08-04 2014-11-19 辽宁亿灵科创生物医药科技有限公司 一种新型海藻提取物组合物在预防病毒性感冒中的应用
CN105412913B (zh) * 2015-12-17 2019-05-14 齐鲁工业大学 一种鼻腔润湿剂
CN105381454B (zh) * 2015-12-17 2019-05-14 齐鲁工业大学 一种含海藻糖的鼻腔润湿剂
WO2021210648A1 (fr) * 2020-04-17 2021-10-21 Next21 Kabushiki Kaisha Médicament contenant du tréhalose ou un dérivé de tréhalose et vaporisateur nasal
US20240197771A1 (en) * 2021-06-17 2024-06-20 Harshita PANT Compositions and uses thereof

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1235846A (zh) * 1998-05-20 1999-11-24 北京金源东和化学有限责任公司 通过鼻粘膜给药的药物制剂
WO2003049747A1 (fr) * 2001-12-12 2003-06-19 Ursapharm Arzneimittel Gmbh & Co. Kg Composition pharmaceutique pour une utilisation ophtalmologique et rhinologique
CN1451389A (zh) * 2002-04-16 2003-10-29 株式会社Cac 促进细胞活化的外用剂
CN1651090A (zh) * 2004-11-30 2005-08-10 中国海洋大学 含海藻糖和玻璃酸的眼部用药传递系统及其制备方法

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1235846A (zh) * 1998-05-20 1999-11-24 北京金源东和化学有限责任公司 通过鼻粘膜给药的药物制剂
WO2003049747A1 (fr) * 2001-12-12 2003-06-19 Ursapharm Arzneimittel Gmbh & Co. Kg Composition pharmaceutique pour une utilisation ophtalmologique et rhinologique
CN1451389A (zh) * 2002-04-16 2003-10-29 株式会社Cac 促进细胞活化的外用剂
CN1651090A (zh) * 2004-11-30 2005-08-10 中国海洋大学 含海藻糖和玻璃酸的眼部用药传递系统及其制备方法

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013041696A1 (fr) * 2011-09-21 2013-03-28 F. Holzer Gmbh Spray nasal et gouttes nasales ayant un effet stimulant et tonifiant
CN112006987A (zh) * 2019-12-13 2020-12-01 吉林省健敷鼻科技有限公司 一种治疗鼻炎的冷敷凝胶及其之制备方法
CN112006987B (zh) * 2019-12-13 2023-04-28 吉林省健敷鼻科技有限公司 一种治疗鼻炎的冷敷凝胶及其之制备方法
IT202100021659A1 (it) * 2021-08-10 2023-02-10 A&R Pharma Srl Composizione topica e suo uso per il trattamento nasale della rinite

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