WO2006066500A1

WO2006066500A1 - The preparation process of quinazoline derivatives and application for the manufacture for the treatment of tumor disease

Info

Publication number: WO2006066500A1
Application number: PCT/CN2005/002253
Authority: WO
Inventors: Peixue Ling; Xiaohua Rong; Lijun Hou; Tianmin Zhang
Original assignee: Peixue Ling; Xiaohua Rong; Lijun Hou; Tianmin Zhang
Priority date: 2004-12-20
Filing date: 2005-12-20
Publication date: 2006-06-29
Also published as: CN1660441A; CN1285382C

Abstract

Provided are quinazoline derivatives of the compound (`) , and its preparation process and application as a medicine of inhibit tumor growth. The group X,Y,Z,R1,R2,R3,R4 of compound (`) are defined in the description. Compounds of the invention can specially inhibit tyrosine kinase activity, adjust VEGF secretion, thus to achieve the purpose of treating malignant tumor.

Description

Nasal medication containing trehalose and hyaluronic acid

Transfer system and preparation method thereof

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. Background technique

Conventional nasal topical preparations have obvious disadvantages. For example, after the traditional nasal drops are dripped, the drug is quickly lost, which makes the bioavailability of the drug low, and even if it is short-lived, it is sometimes difficult to achieve the desired effect. In addition, some nasal drops and nasal sprays have the disadvantages of strong irritation or instability or high systemic absorption toxicity. These have restricted the application and development of traditional nasal medications. In order to solve these problems, people hope to study and apply the nasal drug delivery system (English: de lvery sys tem) to improve the above deficiencies.

According to the traditional deficiency of nasal nasal administration, it is envisaged that 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. Summary of the invention It is an object of the present invention to provide a novel nasal delivery system comprising trehalose and a pharmaceutically acceptable salt of hyaluronic acid and/or hyaluronic acid and a conventional pharmaceutical adjuvant acceptable for nasal administration.

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. Preferably, 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 betamethasone sodium phosphate; the antiallergic agent is preferably sodium cromoglycate; the vasoconstrictor is preferably selected from norepinephrine, serazoline hydrochloride, hydrochloric acid Ephedrine and imidazolidine; the local anesthetic is preferably procaine; the symptom relief agent is preferably selected from the group consisting of zinc sulfate, sodium heparin, oxymetazoline and carteolol hydrochloride; Selected from the group consisting of urinary steroid, chitosan and its derivatives and chondroitin sulfate; the other pharmacologically active ingredients are preferably selected from the group consisting of amino acids, peptides, phospholipids, cellulose ethers, polyethylenol, polyacrylic acid, dextran , vitamin A, carbomer, polyvinylpyrrolidone, cholesterol and dextromethorphan hydrobromide.

In the above nasal drug delivery system, the pharmacologically active ingredient may be one or a plurality of different types or a plurality of different classes.

In the nasal drug delivery system of the present invention, preferably in a 100 ml or 100 g nasal delivery system, 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:

If all the ingredients in the formula are soluble in water, according to the formulation and dosage of the nasal drug delivery system of the present invention, 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. After the solution is cooled, 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;

If all the ingredients in the formulation are soluble in water or have water-insoluble ingredients, according to the formulation and dosage of 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-甾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, hyaluronic acid and conventional pharmaceutical preparation excipients.

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:

Anti-drying properties ("water substitution" effect): 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.

Stabilizing the role of biofilm: Human nasal mucosa is also a biofilm. 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.

The role of preparation stabilizers and preservatives: Trehalose has been widely used as a formulation stabilizer and preservative, which is unmatched by other carbohydrates.

It can be seen from the above that 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. :

Intelligent moisturizing effect: 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.

Lubrication: 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.

Repair and promote healing: 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.

Sustained release: 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.

It can be seen from the above that: 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. Among them, 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. Preferably, 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 drugs such as sodium cromoglycate, ketotifen, etc.; vasoconstrictors such as norepinephrine, seromazole hydrochloride Oral anesthetics such as procaine; symptom relief drugs such as zinc sulfate, heparin sodium, oxymetazoline, naphazoline hydrochloride, carteolol hydrochloride, etc.; Healing hormone Chitosan and its derivatives, chondroitin sulfate, etc.; other pharmacologically active ingredients such as amino acids, peptides, phospholipids, celluloses, polyvinyl alcohol, polyacrylic acid, dextran, vitamin A, carbomer, polyvinylpyrrolidone, Cholesterol, dextromethorphan hydrobromide, Chinese medicine, etc.

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. Condensation agent (ge l ); bone agent (s lurry); ointment (ointment); Fu L cream (cream) and so on.

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. 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. 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. 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. When the nasal delivery system of the present invention is formulated into a milk bone, the commonly used substrates are: petrolatum, lanolin, stearic acid and the like.

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.

Conventional preservatives such as hydroxyphenylethyl ester, thimerosal, EDTA and the like may also be added to the nasal delivery system of the present invention.

More specifically, 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. From water to volume, 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. For the purpose of efficacy; for nasal drug delivery system, can significantly improve the ability of nasal tissue against external dry, freezing and other harsh environments, lubrication and moisturizing nasal tissue; facilitate drug absorption; enhance drug stability; extend the shelf life of the formulation; The retention time of the drug on the surface of the nasal cavity, improve the bioavailability of the drug, and play a long-acting and sustained-release effect; and can reduce the toxic side effects of the drug; reduce the irritancy of the drug solution; improve the comfort of the nose; 4 trehalose is Chemically inert substance, glass acid is basically a chemically inert substance, which can be used for the transmission of various pharmacologically active ingredients, and is used for controlling dry rhinitis, atrophic rhinitis, allergic rhinitis, hypertrophic rhinitis, nose bleeding, sinusitis, etc. Various nasal diseases or systemic diseases.

The molecular structure of trehalose is as follows

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. detailed description

Formulation example

Example 1:

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 .

Example 2:

克克, hydroxyphenylethyl ester 0. 03 g, gram of sodium silicate, 0. 10 g, sodium silicate, 0. The rest is purified water and prepared as a solution.

Example 3:

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.

Example 5

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.

Example 6:

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.

Example 7

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.

Example 8

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.

Example 9

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.

Example 10

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.

Example 11

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.

Example 12:

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.

Example 13

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.

Example 14

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.

Example 15

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:

Thirty healthy subjects were randomly divided into 3 groups, the traditional 1.5% dextromethorphan hydrobromide nasal drops (control group 1), and 1.5% hydrobromic acid containing 0.1% sodium hyaluronate. Methadine nasal drops (control group 2) and the 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.

(x) , half-life (Λ / ₂ ) and area under the curve UO, to investigate the effect of trehalose and hyaluronic acid on the bioavailability of dextromethorphan hydrobromide nasal drops.

The results are shown in Table 1.

Example 13 Pharmacokinetic parameters of dextromethorphan hydrobromide nasal drops

Group x (ng/ml) (min) AUC (rain. ng/ml) Control group 7.9 ± 3· 2 176.1 ± 62.2 1002.3 soil 293.1 Control group 2 10.1 ± 1.8 · 200.2 ± 22.4' 1416.2 ± 134. V Control 3 groups 9.2 ± 1· 5 · 185.3 ± 20.6 1328.1 ± 208.2 · Example 13 12.6 ± 2.8· ^Δ ' 221.7 + 53.2 · ^Δ 1760.6 ± 325.3 · ^Δ '

' Household <0.05, compared with the control group 1, there was a significant difference; ^ corpse <0.05, compared with the control group 2, there was a significant difference; ^#尸<0.05, compared with the control group 3, there was a significant difference

As can be seen from Table 1, the application of trehalose and sodium hyaluronate alone can increase the peak concentration (c _max ) of the drug, the abiotic half-life (and the area under the concentration-time curve, and significantly improve the bioavailability of the drug, However, the combined effect of the two is better, which is significantly better than the application of sodium hyaluronate or trehalose alone. This is mainly due to the action of trehalose-stable biofilm and the adhesion, bioadhesion, spreading and sustained release of hyaluronic acid. Test Example 2:

Traditional chloramphenicol nasal drops have a significant disadvantage: chloramphenicol is easily degraded into diols and fails, and the formulation has a short expiration date. We investigated the stability of the formulation of Example 3 of the present invention with a conventional chloramphenicol nasal drop containing no trehalose and sodium hyaluronate (accelerated test and long-term test).

Accelerated test: 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.

Long-term test: 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%. For the month, 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.

The results are shown in Table 2 and Table 3 Table 2 The results of the chloramphenicol accelerated test of the preparation of Example 3

(temperature 40 °C ± 2 °C relative humidity 20% soil 2%)

Traditional chloramphenicol nasal drops Example 3

Time chloramphenicol accounted for degradation product diol chloramphenicol accounted for

Percentage of chloramphenicol as a percentage of chloramphenicol

0 0. 01 100. 01 0. 01

1 98. 13 1. 77 99. 93 0. 06

2 2. 96 99. 86 0. 13

3 95. 77 4. 20 0. 51

4 94. 55 5. 46 99. 00 0. 99

5 93. 12 6. 86 98. 76 1. 23

6 92. 03 7. 96 98. 65 1. 34 Table 3 Test results of long-term test of chloramphenicol in the preparation of Example 3

(temperature 25 °C ± 2 °C, relative humidity 60% ± 10%)

Traditional chloramphenicol nasal drops Example 3

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

0 100. 02 0. 01 100 • 01 0. 01

1 99. 90 0. 13 99. 92 0. 08

2 98. 01 1. 98 99. 91 0. 10

3 97. 38 2. 62 99. 76 0. 24

4 96. 57 3. 43 99. 67 0. 31

5 96. 02 3. 96 99. 56 0. 44

6 95. 65 4. 34 99. 51 0. 50

7 94. 83 5. 16 99. 45 0. 56

8 94. 15 5. 75 99. 37 0. 62

9 93. 67 6. 32 99. 28 0. 71

10 93. 01 7. 00 99. 16 0. 84

11 92. 45 7. 56 98. 69 1. 30

12 92. 17 7. 82 98. 38 1. 62

13 92. 01 8. 01 98. 06 1. 95

14 91. 13 8. 86 97. 56 2. 43

15 90. 24 9. 75 97. 11 2. 89

16 89. 11 1 0. 88 96. 68 3. 31

17 88. 08 11. 91 96. 47 3. 53

18 87. 18 12 . 82 96. 19 3. 81 As can be seen from Tables 2 and 3, the formulation of 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.

Research data of the present invention 3 :

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.

Table Example 2 Evaluation of the efficacy of the preparation of the method for the treatment of dry rhinitis group |j number of patients cure rate (%) improvement rate (%) inefficiency (%) saline 50 16 20 64 common commercial compound thin

50 36 40 24 Nasal drops

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.

Claims

A nasal drug delivery system characterized by comprising trehalose and a pharmaceutically acceptable salt of a glass acid and/or a glass acid, and a conventional pharmaceutical adjuvant acceptable for nasal administration.

2. The nasal drug delivery system according to claim 1, further comprising one or more pharmacologically active ingredients, wherein the pharmacologically active ingredient may be selected from the group consisting of an antimicrobial agent, a non-steroidal anti-inflammatory drug, and an adrenocortical hormone. a drug, an antiallergic drug, a vasoconstrictor, a local anesthetic, a symptom relief drug, a healing promoting drug, and other pharmacologically active ingredients, the pharmacologically active ingredient may be one or a plurality of different types or different categories Kind.

3. The nasal drug delivery system according to claim 2, wherein the antimicrobial drug is an antibiotic drug, preferably selected from the group consisting of chloramphenicol, gentamicin sulfate, lincomycin, and rifampicin; Or a quinolone, preferably selected from the group consisting of norfloxacin, levofloxacin, ofloxacin, ciprofloxacin, lomefloxacin, rufloxacin, fleroxacin and pefloxacin; or sulfonamide a drug, preferably sulfadiazine; or an antiviral drug, preferably selected from the group consisting of acyclovir, adenosine and ribavirin; wherein the non-steroidal anti-inflammatory drug is preferably selected from the group consisting of diclofenac sodium, piroxicam and melo The adrenocortical hormone is preferably selected from the group consisting of dexamethasone sodium phosphate, dexamethasone acetate, hydrocortisone, and betamethasone sodium phosphate; the antiallergic drug is preferably sodium cromoglycate; Preferably, it is selected from the group consisting of norepinephrine, seroxazoline hydrochloride, ephedrine hydrochloride and imidazolidine; the local anesthetic is preferably procaine; the symptom relief agent is preferably selected from the group consisting of zinc sulfate, heparin sodium, and hydroxymethyl Oxazoline, Naphthyloxaline hydrochloride and carteolol hydrochloride; the damage-inducing healing agent is preferably selected from the group consisting of allantoin, chitosan and derivatives thereof, and chondroitin sulfate; and the other pharmacologically active ingredients are preferably selected from the group consisting of amino acids and peptides. Classes, phospholipids, cellulose ethers, polyvinyl alcohol, polyacrylic acid, dextran, vitamins humans, carbomers, polyvinylpyrrolidone, cholesterol and dextromethorphan hydrobromide.

The medicinal delivery system of the nasal cavity according to any one of claims 1 to 3, wherein the component is trehalose 0.11 ~ 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 supplements.

The nasal drug delivery system according to any one of claims 1 to 4, which is a solution preparation, a gel preparation, a dispersion preparation, a paste or an ointment.

A method of preparing a nasal drug delivery system according to any one of claims 1 to 5, the method comprising:

If all the ingredients in the formula are soluble in water, according to the formulation and dosage of the nasal drug delivery system of the present invention, 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, add other pharmacologically active ingredients to dissolve. After the solution is cooled, add trehalose and a glass acid solution, and then add purified water 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;

7. The use of trehalose in combination with a pharmaceutically acceptable salt of hyaluronic acid and/or a glass acid for the preparation of a nasal delivery system for the treatment and prevention of dry rhinitis and nasal cleansing.

8. Use of trehalose in combination with a pharmaceutically acceptable salt of a glass acid and/or a glass acid for the preparation of a nasal delivery system for promoting the delivery and stability of other pharmacologically active ingredients for the treatment of dryness Rhinitis, atrophic rhinitis, allergies Various nasal diseases or systemic diseases such as rhinitis, hypertrophic rhinitis, nose bleeding, sinusitis; the pharmacologically active ingredients are selected from the group consisting of an antimicrobial agent, a non-steroidal anti-inflammatory drug, an adrenocortical hormone drug, and an antiallergic drug. , vasoconstrictors, local anesthetics, symptom relief drugs, healing agents, and other pharmacologically active ingredients.

9. A method of treating or preventing thousand rhinitis, atrophic rhinitis, allergic rhinitis, hypertrophic rhinitis, nosebleeds, sinusitis, and stability, including administering a patient having such a need according to any one of claims 1 to 5. The nasal drug delivery system of the item.

a method for promoting the delivery and stability 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 drug delivery system is used for treating various nasal diseases or systemic diseases such as dry rhinitis, atrophic rhinitis, allergic rhinitis, hypertrophic rhinitis, nose bleeding, sinusitis; the pharmacologically active ingredient is selected from the group consisting of an antimicrobial agent, a non- Steroidal anti-inflammatory drugs, adrenocortical hormone drugs, antiallergic drugs, vasoconstrictors, local anesthetics, symptom relief drugs, healing agents, and other pharmacologically active ingredients.