CN103599547A

CN103599547A - Nitric oxide donor type non-steroidal anti-inflammatory drug beta-cyclodextrin or beta-cyclodextrin derivative inclusion compound as well as preparation method and application thereof

Info

Publication number: CN103599547A
Application number: CN201310655243.4A
Authority: CN
Inventors: 张恺; 薛娜; 石晓伟; 杜玉民
Original assignee: Hebei Medical University
Current assignee: Hebei Medical University
Priority date: 2012-12-06
Filing date: 2013-12-06
Publication date: 2014-02-26
Anticipated expiration: 2033-12-06
Also published as: CN103599547B

Abstract

The invention provides a nitric oxide donor type non-steroidal anti-inflammatory drug beta-cyclodextrin or beta-cyclodextrin derivative inclusion compound as well as a preparation method and an application thereof. The nitric oxide donor type non-steroidal anti-inflammatory drug beta-cyclodextrin or beta-cyclodextrin derivative inclusion compound comprises a nitric oxide donor type non-steroidal anti-inflammatory drug and beta-cyclodextrin or a beta-cyclodextrin derivative, wherein the molar ratio of the nitric oxide donor type non-steroidal anti-inflammatory drug to beta-cyclodextrin or the beta-cyclodextrin derivative is 1: 1-1: 25. The inclusion compound has high bioavailability and good stability. The preparation method of the inclusion compound, provided by the invention, has the advantages that that the complete separation of the inclusion compound from medicinal raw materials which are not included is realized, the medicinal raw materials which are not included can be completely recycled, and the cost is reduced. The inclusion rate of the preferable preparation method reaches above 70%.

Description

Nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug) beta-schardinger dextrin-or derivatives thereof clathrate and its production and use

Technical field

The invention belongs to medical technical field, be specifically related to a kind of nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug) beta-schardinger dextrin-or derivatives thereof clathrate and its production and use.

Background technology

Since S.Dentin in 1903 successfully obtains beta-schardinger dextrin-(β-CD) first from fermentation liquid, research worker has obtained huge progress at the aspects such as preparation, character and application of cyclodextrin, particularly nearly two, 30 years, the application in pharmaceuticals industry of cyclodextrin and derivant thereof got most of the attention.Medicine cyclodextrin clathrate demonstrates unique character and using value day by day at aspects such as improving drug solubility, dissolution rate, bioavailability.In recent years, cyclodextrin inclusion technique has become the effective means that strengthens drug bioavailability in pharmaceuticals industry, and abroad existing numerous medicine cyclodextrin clathrate preparations successfully go on the market.

Beta-schardinger dextrin-(β-CD) is the earliest by the official oral pharmaceutic adjuvant of a plurality of countries, its medicinal inclusion compound preparation as: prostaglandin beta-CD inclusion, piroxicam beta-CD inclusion etc. successfully go on the market in Japan and Europe.By the β-cdderivatives of structure optimization, in strengthening medicine water solublity, slow controlled release, targeting, transdermal and mucoadhesive delivery system, be also widely used, and become the new focus of excipient substance research.Wherein sulfobutyl ether-beta-cyclodextrin (SBE-β-CD) and HP-β-CD (HP-β-CD) are the β-cdderivatives of outbalance, the features such as the two all has water solublity large (>50g/100ml), nephrotoxicity is low, haemolysis is little, safety is high, are considered to desirable injection supplementary material.

Nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug) is the new direction of NSAID (non-steroidal anti-inflammatory drug) development, and this class medicine has classical NSAID (non-steroidal anti-inflammatory drug) and NO supplies body structure.This class medicine is by the inhibited and onset of epoxidase (COX); at stomach mucosa, discharge the NO of low concentration simultaneously; the NO of low concentration plays protection alimentary canal mucous membrane; increase alimentary canal mucous membrane capillary blood flow; promote the effect of mucosa damaged part injury repairing, thereby reduce traditional NSAIDs, suppress the damage that epoxidase (COX) is produced digestive tract.

At present, more with the nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug) in clinical research stage before clinical, in these drug molecules, comprised that NO is shown in Fig. 1 and Fig. 2 for body structure (nitrate structure and furazan nitrogen oxide structure etc.) more.Existence due to the less NO confession body structure of these polarity, the poorly water-soluble of this type of drug molecule, bioavailability is low, and some drugs raw material becomes oily, more difficultly realize stable preparation and produce, as completed the HCT 3012 (Naproxcinod) of three phases clinical research.

HCT 3012 (Naproxcinod), chemical name is: (S)-2-(6-methoxyl group-2-naphthyl) propanoic acid-4-nitroxide butyl ester, being the non-steroid antiinflammatory of French NicOx company exploitation, is the novel osteoarthritis cushion of the first cyclooxygenase inhibition nitric oxide donors (CINODs).The chemical constitution of HCT 3012 comprises butyl nitrate structure, and with conventional medicament comparison, its mechanism of action is unique, by epoxidase (COX) is inhibited, onset, simultaneously at the NO of stomach mucosa release low concentration, is played the effect of protection gastrointestinal mucosa.HCT 3012 is without the side effect of gastrointestinal side effect and cardiovascular aspect, therefore, the predicted pound bullet level medicine of attaching most importance to of this medicine, market is expected high.HCT 3012 can be hydrolyzed to naproxen, nitrate and other metabolites in blood and intestinal, and due to the existence of nitrate structure, HCT 3012 drug molecule is fat-soluble strong, poorly water-soluble, crude drug is oily, exists bioavailability low, poor stability, the problems such as preparation difficulty.Foreign literature report, HCT 3012 oral formulations adopts one or more adjuvants and oily crude drug to stir by long-time, and the method that forms physical mixture makes.Though the method is successfully by HCT 3012 crude drug solid powdering, production process is difficult to guarantee product quality homogenization, also cannot fundamentally improves the bioavailability of this medicine.

At present, in prior art, the preparation method of cyclodextrin clathrate is generally saturated water solution method and polishing.Utilize above-mentioned two kinds of methods, although can carry out cyclodextrin inclusion compound to nitric oxide donator type nonsteroidal anti-inflammatory drug, have some technical barriers.First; the difficult water-soluble solid of nitric oxide donator type nonsteroidal anti-inflammatory drug or oily liquids; above-mentioned two kinds of methods; before separation; the clathrate of preparation is present in enclose system jointly with solid form and the nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug) of enclose not, and not enclose medicine and the clathrate solid of oily or solid very easily stick, separation difficulty; let alone recycling, therefore cannot accomplish scale production.The second, the medicine of enclose and clathrate do not stick, and are difficult for thoroughly separatedly, cause the clathrate uniformity to decline, and then the accuracy that feeds intake while affecting preparation, cause into the problems such as the property of medicine is poor, preparation stability is poor, solid preparation dissolution is poor.The 3rd, use above-mentioned two kinds of prior aries, envelop rate is low; For improving nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug) envelop rate, need to significantly increase cyclodextrin use amount.But do like this, can reduce clathrate drug loading.Preliminary experimental result shows: utilize above-mentioned existing method to carry out enclose to nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug), inclusion rate < 20%, drug loading < 1.0%.Too low drug loading is unsuitable for preparation and produces.Because: the too low consumption of clathrate in preparation that causes of drug loading increases, and has increased cost; Too low drug loading also make the quality of unit formulation or volume excessive, cause and use inconvenience, reduced patient's compliance.

Summary of the invention

In order to overcome the defect of prior art, the invention provides nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug) beta-schardinger dextrin-or derivatives thereof clathrate and its production and use.Adopt beta-schardinger dextrin-or derivatives thereof to carry out enclose to nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug), increase this type of drug bioavailability, can make especially the solidification of oily nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug) crude drug.With the physical mixture comparison that crude drug and pharmaceutical adjunct form, clathrate stability of the present invention is better, and water solublity is strong, and bioavailability is high, is more suitable for using in pharmaceutical preparation.

Above-mentioned purpose of the present invention realizes by the following technical solutions.

On the one hand, the invention provides a kind of nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug) beta-schardinger dextrin-or derivatives thereof clathrate, it contains nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug) and beta-schardinger dextrin-or beta-cyclodextrin derivative, and wherein the mol ratio of nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug) and beta-schardinger dextrin-or beta-cyclodextrin derivative is 1:1～1:25.

Preferably, the mol ratio of nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug) and beta-schardinger dextrin-or beta-cyclodextrin derivative is 1:1～1:10.

Preferably, described nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug) beta-schardinger dextrin-or derivatives thereof clathrate Subjective and Objective molecular proportion is 1:2 or 1:1.

In aforementioned nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug) beta-schardinger dextrin-or derivatives thereof clathrate, described nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug) is selected from a kind of in the compound with following general structure:

Wherein, X is-(CH ₂) _n1-Z-(CH ₂) _n2, n wherein ₁, n ₂be selected from independently of one another 0,1,2,4 or 5;

Z=O, N, S, C,

or wherein, A=O, N, S, C; Y=

This anti-inflammatory agent has classical NSAID (non-steroidal anti-inflammatory drug) basic structure and NO supplies body structure, wherein, classical NSAID (non-steroidal anti-inflammatory drug) basic structure is selected from salicylic acid structure, aryl alkanamine structure, ortho-aminobenzoic acid structure, arylpropionic acid structure, heteroauxing structure, 2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide structure, but be not limited to this; NO is selected from nitrate structure and furazan nitrogen oxide structure for body structure, but is not limited to this.

Preferably, described nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug) is selected from HCT 3012 (Naproxcinod), 2-(acetoxyl group) benzoic acid-3-(nitroxymethyl) phenyl ester (NCX-4016), 2-(acetoxyl group) benzoic acid-4-(nitroxymethyl) phenyl ester (NCX-4040), 2-(acetoxyl group) benzoic acid-2-(nitroxymethyl) phenyl ester (NCX-4060) or 2-(acetoxyl group) benzoic acid-2-(2-nitrooxy ethyoxyl) ethyl ester (NCX-4018); HCT 3012 more preferably.The structural formula of above-claimed cpd is as follows:

Preferably, described beta-cyclodextrin derivative is selected from HP-β-CD, sulfobutyl ether-beta-cyclodextrin, hydroxyethyl-β-cyclodextrin, dihydroxypropyl-beta-schardinger dextrin-, first group-beta-cyclodextrin, carboxymethyl-beta-cyclodextrin; More preferably the HP-β-CD or the sulfobutyl ether-beta-cyclodextrin that as pharmaceutic adjuvant, use.In addition,, when forming clathrate, enclose material beta-schardinger dextrin-is also preferred.

Nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug)-beta-schardinger dextrin-or derivatives thereof clathrate of the present invention, aspect water solublity, has increased the dissolubility of nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug) in water owing to forming clathrate; Aspect stability, under long-term stable experiment and accelerated test condition, nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug) Benexate Hydrochloride or derivatives thereof is compared with crude drug before enclose, and its water solublity and stability are all better than the front crude drug of enclose.

On the other hand, the present invention also provides a kind of method of preparing aforesaid nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug) beta-schardinger dextrin-or derivatives thereof clathrate, comprising:

I. the described nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug) of oily or solid is first dissolved in organic solvent, adds enclose auxiliary agent, vigorous stirring, ultrasonic or grind under, carry out enclose with beta-schardinger dextrin-or beta-cyclodextrin derivative aqueous solution; Or

II. the described nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug) of oily, adds enclose auxiliary agent, vigorous stirring, ultrasonic or grind under, carry out enclose with beta-schardinger dextrin-or beta-cyclodextrin derivative aqueous solution;

Wherein, described enclose auxiliary agent is selected from one or more in quaternary ammonium enclose auxiliary agent, crown ether-like enclose auxiliary agent or polyethylene glycols enclose auxiliary agent;

Described organic solvent be selected from the organic solvent not miscible with water or with the organic solvent of water immiscible phase.

Preferably, described quaternary ammonium enclose auxiliary agent is selected from one or more in tetrabutyl ammonium bromide, cetyl trimethyl ammonium bromide, benzyltriethylammoinium chloride or benzyl tributyl ammonium chloride; More preferably tetrabutyl ammonium bromide or benzyltriethylammoinium chloride;

It is (C that described crown ether-like enclose auxiliary agent is selected from general formula ₂h ₄o-) _ncompound, wherein, the natural number that n is 1-6; One or more in 15-crown ether-5, hexaoxacyclooctadecane-6-6,12-crown ether-4, dicyclohexyl hexaoxacyclooctadecane-6-6 or dibenzo hexaoxacyclooctadecane-6-6 more preferably;

Described polyethylene glycols enclose auxiliary agent is selected from one or more in PEG-400, PEG-600, PEG-1000, PEG-1500, PEG-4000 or PEG-6000; More preferably PEG-400 and PEG-6000.

Preferably, described enclose auxiliary agent use amount is the 0.1%-10% of described nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug) quality, more preferably 0.1-5%.

Preferably, the not miscible organic solvent of described and water is selected from ethyl acetate, methyl acetate, isopropyl acetate, butyl acetate, dichloromethane, 1,2-dichloroethanes, toluene, benzene, petroleum ether, normal hexane; More preferably ethyl acetate or dichloromethane;

Mass ratio: described nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug): organic solvent=1:1～1:65 that described and water is not miscible.

Preferably, described and organic solvent water immiscible phase is selected from methanol, ethanol, isopropyl alcohol, acetone, propylene glycol, ethylene glycol and glycerol; More preferably ethanol, isopropyl alcohol and glycerol;

Mass ratio: described nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug): the organic solvent=1:2～1:10 of described and water immiscible phase.

As the preferred implementation of above-mentioned preparation method, the invention provides a kind of method of preparing aforesaid nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug) beta-schardinger dextrin-or derivatives thereof clathrate, specifically comprise the steps:

(1) get the described nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug) of oily or solid, what add 1～65 times of quality makes its dissolving with the not miscible organic solvent of water;

(2) according to mol ratio, get beta-schardinger dextrin-or beta-cyclodextrin derivative, add 10～350 times of mole distilled water, heated and stirred is to dissolving completely;

(3) after two kinds of solution that above-mentioned

steps

1 and 2 obtained mix, add described nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug) quality 0.1%-10%, be preferably the described enclose auxiliary agent of 0.1-5%, vigorous stirring, ultrasonic or grinding 10-60min;

(4) solution left standstill step 3 being obtained, separatory, organic facies is evaporated to dry, obtains not by the nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug) of enclose;

(5) aqueous solution step 4 separation being obtained is dry with organic solvent washing postlyophilization described and that water is not miscible or spraying, obtains nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug) beta-schardinger dextrin-or derivatives thereof clathrate.

As the another kind of preferred implementation of above-mentioned preparation method, the invention provides a kind of method of preparing aforesaid nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug) beta-schardinger dextrin-or derivatives thereof clathrate, specifically comprise the steps:

(1) get the described nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug) of oily or solid, add the organic solvent of the described and water immiscible phase of 2～10 times of quality, ultrasonic 10～20min;

(2) according to mol ratio, get beta-schardinger dextrin-or beta-cyclodextrin derivative, add the distilled water of 20～100 times of moles, enclose material beta-schardinger dextrin-or beta-cyclodextrin derivative are dissolved completely;

(3) step 1 and step 2 are obtained to two kinds of solution mixing, add described nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug) quality 0.1%-10%, be preferably the enclose auxiliary agent of 0.1-5%, vigorous stirring, ultrasonic or grinding 30min-2h, steam organic solvent described and water immiscible phase under decompression;

(4) the nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug) to oily, by the remaining solution left standstill 20～40min of step 3, directly separated and reclaim lower floor's oily not by the nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug) of enclose; Nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug) to solid, by the filtration of step 3 residue, reclaims filtering residue, obtain solid not by the nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug) of enclose;

(5) the aqueous solution lyophilization or the spray drying treatment that step 4 separation are obtained, obtain nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug) beta-schardinger dextrin-or derivatives thereof clathrate.

As the another kind of preferred implementation of above-mentioned preparation method, the present invention also provides a kind of method of preparing aforesaid nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug) beta-schardinger dextrin-or derivatives thereof clathrate, specifically comprises the steps:

(1) get the described nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug) of oily, add the distilled water of 1～25 times of quality and beta-schardinger dextrin-or the beta-cyclodextrin derivative of 1～25 times of mole, add again described nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug) quality 0.1%-10%, be preferably the enclose auxiliary agent of 0.1-5%, vigorous stirring, ultrasonic or grinding 20min-2h;

(2) add the distilled water of 10～350 times of moles of described nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug), stir 10～30min, standing 20～40min, separatory, direct separation is also reclaimed lower floor not by the nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug) of enclose; Or,

Add 10～150 times of quality with the not miscible organic solvent of water, stir 10～30min, standing 20～40min, separated organic facies, organic facies is evaporated to dry, obtains not by the nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug) of enclose;

(3) the aqueous solution lyophilization or the spray drying treatment that step 2 separation are obtained, obtain nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug) beta-schardinger dextrin-or derivatives thereof clathrate.

The present invention also provides a kind of method of preparing aforesaid nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug) beta-schardinger dextrin-or derivatives thereof clathrate, specifically comprises the steps:

(1) get the described nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug) of oily or solid, add 1～65 times of quality with the not miscible organic solvent of water, make its dissolving;

(3) two kinds of solution that above-mentioned

steps

1 and 2 obtained mix, vigorous stirring, ultrasonic or grinding 10-60min;

(5) aqueous solution step 4 separation being obtained is with after organic solvent washing described and that water is not miscible, and lyophilization or spraying are dry, obtain nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug) beta-schardinger dextrin-or derivatives thereof clathrate;

Wherein, the not miscible organic solvent of described and water is selected from ethyl acetate, methyl acetate, isopropyl acetate, butyl acetate, dichloromethane, 1,2-dichloroethanes, toluene, benzene, petroleum ether, normal hexane; Be preferably ethyl acetate or dichloromethane.

In addition, the invention provides a kind of method of preparing aforesaid nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug) beta-schardinger dextrin-or derivatives thereof clathrate, specifically comprise the steps:

(1) get the described nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug) of oily or solid, add 2～10 times of quality and organic solvent water immiscible phase, ultrasonic 10～20min;

(3) two kinds of solution that step 1 and step 2 obtained mix, and vigorous stirring, ultrasonic or grind 30min-2h, steams organic solvent described and water immiscible phase under decompression;

(4) the nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug) to oily, by the remaining solution left standstill 20～40min of step 3, directly separated and reclaim lower floor's oily not by the nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug) of enclose; Nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug) to solid, by the remaining filtration of step 3, reclaims filtering residue, obtain solid not by the nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug) of enclose;

(5) the aqueous solution lyophilization or the spray drying treatment that step 4 separation are obtained, obtain nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug) beta-schardinger dextrin-or derivatives thereof clathrate;

Wherein, the miscible organic solvent of described and water is selected from methanol, ethanol, isopropyl alcohol, acetone, propylene glycol, ethylene glycol and glycerol; Be preferably ethanol, isopropyl alcohol and glycerol.

(1) get the described nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug) of oily, add the distilled water of 1～25 times of quality and beta-schardinger dextrin-or the beta-cyclodextrin derivative of 1～25 times of mole, vigorous stirring, ultrasonic or grind 10～60min;

(2) add 10～350 times of mole distilled water, stir 30～60min, add 10～150 times with the not miscible organic solvent of water, stir 20min;

(3) step 2 gained solution is inserted to the standing 20～40min of separatory funnel, separatory, reclaims organic layer extract, and organic layer extract is evaporated to dry, reclaims nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug);

(4) the water lyophilization or the spray drying treatment that step 3 are obtained, obtain nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug) beta-schardinger dextrin-or derivatives thereof clathrate;

(2) add 10～350 times of mole distilled water, stir 10～30min;

(3) by step 2 gained solution left standstill 20～40min, separatory, separated also recovery is not by the nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug) of enclose;

(4) the aqueous solution lyophilization or the spray drying treatment that step 3 separation are obtained, obtain nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug) beta-schardinger dextrin-or derivatives thereof clathrate.

The method that the invention provides the aforesaid nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug) beta-schardinger dextrin-or derivatives thereof clathrate of another kind of preparation, specifically comprises the steps:

(1) get the described nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug) of solid, the beta-schardinger dextrin-or the beta-cyclodextrin derivative that add 1～25 times of mole, add 10～350 times of mole distilled water, be heated to 60-80 ℃ of vigorous stirring, ultrasonic or grind 10～60min;

(2) filtered while hot, reclaims filter cake, obtains not by the nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug) of enclose;

(3) filtrate lyophilization or spray drying treatment, obtain nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug) beta-schardinger dextrin-or derivatives thereof clathrate.

Another aspect, the present invention also provides a kind of pharmaceutical composition, and this pharmaceutical composition comprises aforesaid nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug) beta-schardinger dextrin-or derivatives thereof clathrate and pharmacy adjuvant.

Preferably, described pharmaceutical composition is injection or oral formulations; More preferably, described injection is transfusion, liquid drugs injection or powder injection formulation, for example, be sodium chloride transfusion or glucose infusion liquid; Described oral formulations is oral liquid, syrup, tablet, capsule or granule; Described pharmacy adjuvant is selected from one or more in amylum pregelatinisatum, magnesium stearate, lactose, sucrose, glucose, sodium chloride and sorbitol.

Again on the one hand, the present invention also provide aforesaid nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug) beta-schardinger dextrin-or derivatives thereof clathrate with and pharmaceutical composition for example, in preparation treatment diseases associated with inflammation, the purposes in rheumatic arthritis, rheumatoid arthritis and osteoarthritis.

Compared with prior art, the present invention at least has following useful technique effect:

1. nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug) beta-schardinger dextrin-or derivatives thereof clathrate of the present invention is scattered in solution, with enclose medicine is not separated completely: enclose medicine is not realized recovery on the one hand, reduces costs; Clathrate good evenness on the other hand, stability is high.Therefore the preparation method of nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug) beta-schardinger dextrin-or derivatives thereof clathrate of the present invention, is applicable to suitability for industrialized production.

2. clathrate of the present invention has not only kept the drug effect of nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug), and compares with enclose raw material not, and bioavailability, water solublity, stability significantly improve.In zoopery, oral administration biaavailability is apparently higher than its enclose crude drug not.In the time of 20 ℃, in clathrate water of the present invention, dissolubility is more than 10g/100ml.Therefore, clathrate of the present invention is more suitable for preparation, can be used for the treatment of rheumatic arthritis, rheumatoid arthritis and osteoarthritis and substituting of traditional nonsteroidal anti-inflammatory agent.

3. the present invention carries out enclose with beta-cyclodextrin derivatives such as β-CD and HP-β-CD, SBE-β-CD to novel nitric oxide (NO) donator type NSAID (non-steroidal anti-inflammatory drug), can make the solidification of oily nitric oxide (NO) donator type NSAID (non-steroidal anti-inflammatory drug), the medicine cyclodextrin clathrate of gained can directly apply to the exploitation of solid and liquid pharmaceutical formulation, solve oily nitric oxide (NO) donator type NSAID (non-steroidal anti-inflammatory drug) preparation formulation and be limited to soft capsule, type of preparation is single, the problem that production cost is high.

4. the invention discloses a kind of β of use-CD or β-cdderivatives by the lower nitric oxide donator type nonsteroidal anti-inflammatory drug enclose of bioavailability, improve the bioavailability of this type of pharmaceutical preparation, strengthen medicine stability, improve the water miscible method of medicine.The method is particularly suitable for fat-soluble strong, and crude drug becomes the preparation of nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug) β-CD or the β-cdderivatives clathrate of oily.The method efficiency is high, can realize fast, stable, prepares in large quantities nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug) β-CD or β-cdderivatives clathrate, and enclose medicine can not realized completely and reclaiming, and not treated direct continuation is used.Thereby solve and to limit at present this type of medicine further the bioavailability of exploitation is low, poor stability, is difficult in water, dissolving, cannot developing the difficulty of liquid preparation.

5. the present invention carries out enclose with beta-cyclodextrin derivatives such as β-CD and HP-β-CD, SBE-β-CD to novel nitric oxide (NO) donator type NSAID (non-steroidal anti-inflammatory drug), strengthened medicine stability, clathrate stability, apparently higher than crude drug and physical mixture, is conducive to the long term storage of medicine.

The method of preferably preparing nitric oxide donator type nonsteroidal anti-inflammatory drug cyclodextrin clathrate provided by the invention, promotes Subjective and Objective molecule generation enclose with mechanical force and enclose auxiliary agent catalysis combined effect, has improved inclusion rate, and inclusion rate can reach more than 70%; Saturated water solution method enclose nitric oxide donator type nonsteroidal anti-inflammatory drug enclose weak effect, inclusion rate is lower than 20%.In addition, biphase lock out operation is take in the present invention: 1) clathrate aqueous solution is water, oily nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug) raw material directly for organic facies or dissolve nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug) raw material with the not miscible organic solvent of water be organic facies; 2) clathrate aqueous solution is water, and solid nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug) raw material is solid phase.Realized the completely separated of clathrate and enclose crude drug not, enclose crude drug can be realized completely and reclaiming, and has reduced cost.With lyophilizing or spray drying method, water (clathrate aqueous solution) is cured and processes the product that obtains quality homogeneous.

Preparation method provided by the invention, is especially applicable to oily nitric oxide donator type nonsteroidal anti-inflammatory drug to carry out cyclodextrin inclusion compound.Its technical advantage comprises: 1. nitric oxide donator type nonsteroidal anti-inflammatory drug enclose is effective.2. beta-schardinger dextrin-(β-CD) or beta-cyclodextrin derivative use amount are few, the mol ratio of nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug) and beta-schardinger dextrin-(β-CD) or beta-cyclodextrin derivative is 1:1～1:25, drug loading is high, drug loading > 3.0%(correction data is in Table 2), can realize solid preparation and the liquid preparation preparation of nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug).3. clathrate bioavailability of the present invention is apparently higher than the simple physical mixture of crude drug and adjuvant, solved nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug) poorly water-soluble, because crude drug is oily, cause the problems such as bioavailability is low, poor stability, preparation difficulty, be more suitable in formulation development.4. clathrate process is simple to operate, favorable reproducibility, and stable and reliable product quality, enclose medicine is with the realization of enclose medicine is completely not separated, and enclose crude drug can not realized completely and reclaiming, and has reduced production cost.Therefore, the method for preparing nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug) cyclodextrin clathrate provided by the invention, is suitable for suitability for industrialized production, is the effective way of exploitation nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug) related preparations.

Accompanying drawing explanation

Below, describe by reference to the accompanying drawings embodiment of the present invention in detail, wherein:

Fig. 1 is before clinical and the nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug) I in clinical research stage;

Fig. 2 is before clinical and the nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug) II in clinical research stage;

Fig. 3 is HCT 3012 aqueous solution uv-spectrogram;

Fig. 4 is HCT 3012 methanol solution uv-spectrogram;

Fig. 5 is HP-β-CD aqueous solution uv-spectrogram;

Fig. 6 is HP-β-CD methanol solution uv-spectrogram;

Fig. 7 is HCT 3012-HP-β-CD aqueous solution uv-spectrogram;

Fig. 8 is HCT 3012-HP-β-CD methanol solution uv-spectrogram;

Fig. 9 is HCT 3012 crude drug infrared absorption pattern;

Figure 10 is HP-β-CD infrared absorption pattern;

Figure 11 is HCT 3012-hydroxypropyl-beta-cyclodextrin inclusion infrared absorption pattern;

Figure 12 is HCT 3012-hydroxypropyl-beta-cyclodextrin inclusion infrared absorption pattern;

Figure 13 is before enclose, after enclose and the drug-time curve figure of the HCT 3012 of physical mixture; And

Figure 14 is before enclose, after enclose and the drug-time curve figure of the naproxen of physical mixture (metabolite).

The specific embodiment

Below by embodiment, describe the present invention in detail, should be appreciated that following embodiment is only for the present invention is described, and the scope not limiting the present invention in any way.All technology realizing based on foregoing of the present invention all belong to scope of the present invention.

In the following example, in nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug) used, HCT 3012, NCX-4018 are oilies, and NCX-4016 and NCX-4060 are pulverulent solids.

embodiment 1the preparation of HCT 3012-sulfobutyl ether-beta-cyclodextrin inclusion compound

Take enclose material sulfobutyl ether-beta-cyclodextrin 4kg, add 10L distilled water to be stirred to completely and dissolve; HCT 3012 350g adds in 2L ethyl acetate, stirs completely and dissolves; After being mixed, above-mentioned two solution add tetrabutyl ammonium bromide 1g, and after strong stirring 60min, standing, separatory; Reclaim ethyl acetate layer, ethyl acetate solution is evaporated to the dry not crude drug of enclose that reclaims; The aqueous solution that separation obtains is dry with spraying after ethyl acetate washing (0.5L * 3), obtains loose HCT 3012-sulfobutyl ether-beta-cyclodextrin inclusion compound 3.88kg.Through HPLC method, detect inclusion rate 76%.Reclaim HCT 3012 46.4g.

embodiment 2the preparation of NCX-4060-sulfobutyl ether-beta-cyclodextrin inclusion compound

Take enclose material sulfobutyl ether-beta-cyclodextrin 180g, add 200ml distilled water to be stirred to completely and dissolve, 15g NCX-4060 adds in 50ml dichloromethane, stirs completely and dissolves; After above-mentioned two solution are mixed, add tetrabutyl ammonium bromide 0.2g, after strong stirring 60min, insert separatory funnel, standing, separatory; Reclaim dichloromethane layer extract, dichloromethane extraction liquid is evaporated to the dry not crude drug of enclose that reclaims; After the washed with dichloromethane for aqueous solution (20ml * 3) that separation obtains, spraying is dried, and obtains loose NCX-4060-sulfobutyl ether-beta-cyclodextrin inclusion compound 180.4g.Through HPLC method, detect inclusion rate 86%.Reclaim NCX-40601.1g.

embodiment 3the preparation of NCX-4060-sulfobutyl ether-beta-cyclodextrin inclusion compound

Take enclose material sulfobutyl ether-beta-cyclodextrin 15g, add 120ml distilled water to be stirred to completely and dissolve; 1.5g NCX-4060 adds in 50ml toluene, stirs completely and dissolves; After above-mentioned two solution are mixed, add 0.1g PEG-6000, after strong stirring 60min, move into separatory funnel, standing, separatory; Reclaim toluene layer, toluene solution is evaporated to the dry not crude drug of enclose that reclaims; After the toluene wash for aqueous solution (20ml * 3) that separation obtains, spraying is dried, and obtains loose NCX-4060-sulfobutyl ether--Benexate Hydrochloride 15.2g.Through HPLC method, detect inclusion rate 79.2%.Reclaim 0.21gNCX-4060.

embodiment 4the preparation of NCX-4060-sulfobutyl ether-beta-cyclodextrin inclusion compound

Take enclose material sulfobutyl ether-beta-cyclodextrin 400g, add 1200ml distilled water to be stirred to completely and dissolve; 30g NCX-4060 adds in 1000ml ethyl acetate, stirs completely and dissolves; After above-mentioned two solution are mixed, add tetrabutyl ammonium bromide 0.05g, after strong stirring 60min, move into separatory funnel, standing separatory, reclaims ethyl acetate layer, and ethyl acetate solution is evaporated to the dry not crude drug of enclose that reclaims; The aqueous solution that separation obtains is dry with spraying after ethyl acetate washing (200ml * 3), obtains loose NCX-4060-sulfobutyl ether-beta-cyclodextrin inclusion compound 342g.Through HPLC method, detect inclusion rate 76%.Reclaim NCX-40604.2g.

embodiment 5the preparation of NCX-4016-hydroxypropyl-beta-cyclodextrin inclusion

Take enclose material HP-β-CD 20g, add 100ml distilled water to be stirred to completely and dissolve; 1.5g NCX-4016 adds in 40ml ethyl acetate, stirs completely and dissolves; After above-mentioned two solution are mixed, add 0.1g18-crown ether-6, after strong stirring 50min, move into separatory funnel, standing separatory, reclaims ethyl acetate layer, and ethyl acetate solution is evaporated to the dry not crude drug of enclose that reclaims; Aqueous solution ethyl acetate washing (30ml * 3) postlyophilization that separation obtains 24 hours, obtains loose NCX-4016-hydroxypropyl-beta-cyclodextrin inclusion 16.8g.Through HPLC method, detect inclusion rate 78.5%.Reclaim 0.52g NCX-4016.

embodiment 6 HCT 3012s-the preparation of hydroxypropyl-beta-cyclodextrin inclusion

Take enclose material HP-β-CD 15g, add 150ml distilled water to be stirred to completely and dissolve; 1.5g HCT 3012 adds in 60ml methanol, stirs completely and dissolves; After being mixed, above-mentioned two solution add 0.05g PEG-400, after strong stirring 60min, and evaporated under reduced pressure methanol, surplus solution moves into separatory funnel, standing, separatory; Reclaim the not crude drug of enclose; The aqueous solution spraying that separation obtains is dry, obtains loose HCT 3012-hydroxypropyl-beta-cyclodextrin inclusion 15.4g.Through HPLC method, detect inclusion rate 80.2%.Reclaim 0.25g HCT 3012.

embodiment 7the preparation of NCX-4016-hydroxypropyl-beta-cyclodextrin inclusion

Take enclose material HP-β-CD 15g, add 120ml distilled water to be stirred to completely and dissolve; 1.5g NCX-4016 adds in 50ml ethanol, stirs completely and dissolves; After being mixed, above-mentioned two solution add tetrabutyl ammonium bromide 0.05g, after strong stirring 40min, and evaporated under reduced pressure ethanol, surplus solution filters, and reclaims filtering residue and is the not crude drug of enclose; Filtrate spraying is dry, obtains loose NCX-4016-hydroxypropyl-beta-cyclodextrin inclusion 14.9g.Through HPLC method, detect inclusion rate 83.0%.Reclaim 0.24g HCT 3012.

embodiment 8the preparation of HCT 3012-hydroxypropyl-beta-cyclodextrin inclusion

Take enclose material HP-β-CD 20g, add 20ml distilled water, add HCT 3012 1.5g, stir 30min; Add successively 250ml distilled water and benzyltriethylammoinium chloride 0.05g, vigorous stirring 20min; Then add 50ml ethyl acetate, stir after 10min, move into separatory funnel, standing, separatory; Reclaim ethyl acetate layer, ethyl acetate solution is evaporated to the dry not crude drug of enclose that reclaims; 48h is processed in the aqueous solution lyophilization that separation obtains, and obtains loose HCT 3012-hydroxypropyl-beta-cyclodextrin inclusion 18.2g.Through HPLC method, detect inclusion rate 75%.Reclaim HCT 3012 0.19g.

embodiment 9the preparation of NCX-4018-hydroxypropyl-beta-cyclodextrin inclusion

Take enclose material HP-β-CD 20g, add 30ml distilled water, add NCX-40181.5g, stir 40min; Add 250ml distilled water to stir 20min; Add successively PEG-4000.05g and 40ml dichloromethane, after vigorous stirring 20min, move into separatory funnel, standing, separatory; Reclaim dichloromethane layer, dichloromethane solution is evaporated to the dry not crude drug of enclose that reclaims; The aqueous solution spraying that separation obtains is dry, obtains loose NCX-4018-hydroxypropyl-beta-cyclodextrin inclusion 19.3g.Through HPLC method, detect inclusion rate 73%.Reclaim NCX-40180.24g.

the preparation of embodiment 10 HCT 3012s-hydroxypropyl-beta-cyclodextrin inclusion

Take enclose material HP-β-CD 15g, add 50ml distilled water to be stirred to completely and dissolve; Add 1.5g HCT 3012, add PEG-4000.1g, after strong stirring 60min, move into separatory funnel, standing, separatory, directly the Separation and Recovery lower floor crude drug of enclose not; The aqueous solution spraying that separation obtains is dry, obtains loose HCT 3012-hydroxypropyl-beta-cyclodextrin inclusion 15.8g.Through HPLC method, detect inclusion rate 76.0%.Reclaim 0.30g HCT 3012.

embodiment 11hCT 3012-sulfobutyl ether-beta-cyclodextrin inclusion compound

Take enclose material sulfobutyl ether-beta-cyclodextrin 15g, add 50mL distilled water to be stirred to completely and dissolve; HCT 3012 1.5g adds in 30mL ethyl acetate, stirs completely and dissolves; After strong stirring 60min, standing, separatory; Reclaim ethyl acetate layer, ethyl acetate solution is evaporated to the dry not crude drug of enclose that reclaims; The aqueous solution that separation obtains is dry with spraying after ethyl acetate washing (10mL * 3), obtains loose HCT 3012-sulfobutyl ether-beta-cyclodextrin inclusion compound 13.2g.Through HPLC method, detect inclusion rate 52.2%.Reclaim HCT 3012 0.54g

embodiment 12the preparation of NCX-4016-hydroxypropyl-beta-cyclodextrin inclusion

Take enclose material HP-β-CD 20g, add 120ml distilled water to be stirred to completely and dissolve; 2.0g NCX-4016 adds in 50ml toluene, stirs completely and dissolves; After above-mentioned two solution are mixed, add tetrabutyl ammonium bromide 0.1g, according to strong stirring 40min, after standing 10min, separatory, reclaims the not crude drug of enclose after organic layer evaporated under reduced pressure toluene; The aqueous solution lyophilization that separation obtains 48 hours, obtains loose NCX-4016-hydroxypropyl-beta-cyclodextrin inclusion 21.2g.Through HPLC method, detect inclusion rate 74.8%.Reclaim 0.34g NCX-4016.

embodiment 13the preparation of HCT 3012-sulfobutyl ether-beta-cyclodextrin inclusion compound

HCT 3012 45g, adds acetone 180ml to dissolve, and stirs 20min to dissolving; Take enclose material sulfobutyl ether-beta-cyclodextrin 660g, add 4.5L distilled water, agitating heating under water-bath, dissolves enclose material completely; Under stirring condition, HCT 3012 acetone soln is slowly joined in enclose material water solution to vigorous stirring 20min; In 40 ℃, remove acetone under reduced pressure, surplus solution immigration separatory funnel, standing 20min, the directly separated not HCT 3012 of enclose of lower floor's oily that also reclaims; The aqueous solution lyophilization 48h that separation obtains, obtains loose HCT 3012-sulfobutyl ether-beta-cyclodextrin inclusion compound 602g.Through HPLC method, detect inclusion rate 56%, organic facies concentration and recovery HCT 3012 16.8g.

embodiment 14the preparation of HCT 3012-hydroxypropyl-beta-cyclodextrin inclusion

HCT 3012 1.45g, adds methanol 6ml, and ultrasonic 15min makes to dissolve completely; Take enclose material HP-β-CD 20g, add 150ml distilled water, agitating heating under hot bath, dissolves enclose material completely; Under stirring condition, HCT 3012 methanol solution is slowly joined in enclose material water solution, grind 20min; In 40 ℃, remove methanol under reduced pressure, surplus solution immigration separatory funnel, standing 20min, the directly separated not HCT 3012 of enclose of lower floor's oily that also reclaims; The aqueous solution lyophilization 48h that separation obtains, obtains loose HCT 3012-hydroxypropyl-beta-cyclodextrin inclusion 19.8g.Through HPLC method, detect inclusion rate 60%.Reclaim HCT 3012 0.36g.

embodiment 15the preparation of HCT 3012-hydroxypropyl-beta-cyclodextrin inclusion

HCT 3012 15g, adds methanol 50ml, and rapid stirring 30min is to dissolving; Take enclose material HP-β-CD 200g, add 1500ml distilled water, agitating heating under hot bath, dissolves enclose material completely; Under stirring condition, HCT 3012 methanol solution is slowly joined in enclose material water solution to ultrasonic 30min; In 40 ℃, remove methanol under reduced pressure, surplus solution immigration separatory funnel, standing 40min, the directly separated not HCT 3012 of enclose of lower floor's oily that also reclaims; The aqueous solution lyophilization 48h that separation obtains, obtains loose HCT 3012-hydroxypropyl-beta-cyclodextrin inclusion 207g.Through HPLC method, detect inclusion rate 58.5%.Reclaim HCT 3012 5.2g.

embodiment 16the preparation of NCX-4018-sulfobutyl ether-beta-cyclodextrin inclusion compound

2.0gNCX-4018, adding acetone 12ml, ultrasonic 20min makes to dissolve; Take enclose material sulfobutyl ether-beta-cyclodextrin 25g, add 180ml distilled water, agitating heating under water-bath, dissolves enclose material completely; Under stirring condition, above-mentioned NCX-4018 acetone soln is slowly joined in enclose material water solution to vigorous stirring 20min; In 40 ℃, remove acetone under reduced pressure, surplus solution immigration separatory funnel, standing 30min, the directly separated not NCX-4018 of enclose of lower floor's oily that also reclaims; The aqueous solution lyophilization 48h that separation obtains, obtains loose NCX-4018-sulfobutyl ether-beta-cyclodextrin inclusion compound 23.2g.Through HPLC method, detect inclusion rate 63.0%, reclaim 0.52g NCX-4018.

the preparation of embodiment 17NCX-4016-HP-β-CD

Take enclose material HP-β-CD 20g, add 120ml distilled water to be stirred to completely and dissolve; 2.0g NCX-4016 adds in 50ml methanol, stirs completely and dissolves; After above-mentioned two solution are mixed, add tetrabutyl ammonium bromide 0.2g, according to strong stirring 50min, 40 ℃ remove methanol under reduced pressure, and surplus solution filters, and reclaims filtering residue, obtains the crude drug of the not enclose of solid; The aqueous solution spraying that separation obtains is dry, obtains loose NCX-4016-hydroxypropyl-beta-cyclodextrin inclusion 22.0g.Through HPLC method, detect inclusion rate 78.5%.Reclaim 0.39g NCX-4016.

embodiment 18the preparation of HCT 3012-sulfobutyl ether-beta-cyclodextrin inclusion compound

HCT 3012 8g, adds sulfobutyl ether-beta-cyclodextrin 112g, distilled water 40ml, continuously grinding 20min, adds distilled water 600ml, stirs 10min, add dichloromethane 50ml, stir 10min, move into separatory funnel, standing 20min, separatory, reclaims dichloromethane layer, and dichloromethane solution is evaporated to the dry not HCT 3012 of enclose that reclaims, water layer solution lyophilization 48h, obtains loose HCT 3012-sulfobutyl ether-beta-cyclodextrin inclusion compound 110.5g.Through HPLC method, detect inclusion rate 54.4%.Reclaim HCT 3012 2.54g.

embodiment 19the preparation of HCT 3012-hydroxypropyl-beta-cyclodextrin inclusion

Take 2.0g HCT 3012, add enclose material sulfobutyl ether-beta-cyclodextrin 20g, add 120ml distilled water, according to strong stirring 50min, standing 30min, directly reclaims the not crude drug of enclose after separatory; Water layer spraying is dry, obtains loose HCT 3012-sulfobutyl ether-beta-cyclodextrin inclusion compound 20.2g.Through HPLC method, detect inclusion rate 55.0%.Reclaim 0.39g HCT 3012.

embodiment 20the preparation of NCX-4016-hydroxypropyl-beta-cyclodextrin inclusion

1.2g gets NCX-4016, adds 55g HP-β-CD and 350ml distilled water, is heated to 80 ℃ of vigorous stirring 30min, and filtered while hot reclaims filter cake and obtains not by the NCX-40160.51g of enclose.Filtrate lyophilization 48h, obtains NCX-4016-hydroxypropyl-beta-cyclodextrin inclusion 52.4g, through HPLC method, detects inclusion rate 46.5%.

embodiment 21the preparation of NCX-4060-sulfobutyl ether-beta-cyclodextrin inclusion compound

Get 1.5g NCX-4060, add 55g sulfobutyl ether-beta-cyclodextrin and 350ml distilled water, be heated to 60 ℃ of vigorous stirring 30min, filtered while hot, reclaims filter cake and obtains not by the NCX-40600.42g of enclose.Filtrate lyophilization 48h, obtains NCX-4060-sulfobutyl ether-beta-cyclodextrin inclusion compound 53.2g, through HPLC method, detects inclusion rate 52.0%.

comparative example 1the preparation of NCX-4016-hydroxypropyl-beta-cyclodextrin inclusion

Get 1.2g NCX-4016, add 105g HP-β-CD and 130ml distilled water, be heated to 80 ℃ and stir 30min, while hot membrane filtration.The cooling 8h of filtrate, filters, and filtration cakes torrefaction obtains NCX-4016-hydroxypropyl-beta-cyclodextrin inclusion 62.4g, through HPLC method, detects inclusion rate 13.5%.

comparative example 2the preparation of HCT 3012-hydroxypropyl-beta-cyclodextrin inclusion

Get HP-β-CD 45g, adding distil water, to 50ml, makes to dissolve in 60 ℃ of stirred in water bath; Get HCT 3012 0.5g, use 0.5ml ethanol dilution, under stirring, slowly be added drop-wise in the aqueous solution of the HP-β-CD that heat is saturated, after adding, continue to stir 1.5h, microporous filter membrane heat filtering, to be cooled, put refrigerator cold-storage and spend the night, after 24h, sucking filtration, filter cake ethyl acetate washed twice, drain, put in vacuum drying oven, 45 ℃ dry, obtains HCT 3012-hydroxypropyl-beta-cyclodextrin inclusion 12.4g.Through HPLC method, detect inclusion rate 17.5%.

comparative example 3the preparation of HCT 3012-hydroxypropyl-beta-cyclodextrin inclusion

Take through HP-β-CD 40g and put in mortar, add 5ml distilled water and be ground to pasty state, separately by HCT 3012 0.5g, use 0.5ml ethanol dilution, release in the cyclodextrin that is slowly added drop-wise to pasty state, limit edged grinds, and adds rear continuation and grinds 2h, standing over night, sucking filtration, petroleum ether twice for filter cake, puts in vacuum drying oven, 45 ℃ dry, obtains HCT 3012-hydroxypropyl-beta-cyclodextrin inclusion 8.6g.Through HPLC method, detect inclusion rate 12.5%.

comparative example 4the preparation of 20NCX-4060-hydroxypropyl-beta-cyclodextrin inclusion

Get HP-β-CD 55g, adding distil water, to 80ml, makes to dissolve in 60 ℃ of stirred in water bath, agitator stirs, and gets NCX-40601.5g, is added in the aqueous solution of the HP-β-CD that heat is saturated, after adding, continue to stir 1.5h, microporous filter membrane heat filtering, to be cooled, put refrigerator cold-storage and spend the night, after 24h, sucking filtration, washing with alcohol twice for filter cake, drains, put in vacuum drying oven, 45 ℃ dry, obtains HCT 3012-hydroxypropyl-beta-cyclodextrin inclusion 16.4g.Through HPLC method, detect inclusion rate 7.5%.

comparative example 5the preparation of HCT 3012 and HP-β-CD physical mixture

HCT 3012 1.5g and HP-β-CD 70g put into container, directly stir 30min to crude drug and cyclodextrin mix homogeneously, and gained solid is crossed 100 mesh sieves, obtain HCT 3012 and HP-β-CD physical mixture I 21.1g.

comparative example 6the preparation of HCT 3012 and sulfobutyl ether-beta-cyclodextrin physical mixture

HCT 3012 15g and sulfobutyl ether-beta-cyclodextrin 200g put into mortar, directly stir 30min to crude drug and cyclodextrin mix homogeneously, and gained solid is crossed 100 mesh sieves, obtain HCT 3012 and sulfobutyl ether-beta-cyclodextrin physical mixture I 210.6g.

comparative example 7the preparation of HCT 3012 and amylum pregelatinisatum, sucrose physical mixture

HCT 3012 15g and amylum pregelatinisatum 200g, sucrose 30.0g put into mortar, use agitator rapid stirring 30min to crude drug and adjuvant mix homogeneously, gained solid is crossed 200 mesh sieves, obtains HCT 3012 and amylum pregelatinisatum, sucrose physical mixture II 240.5g.

comparative example 8hCT 3012 and the transfusion of sulfobutyl ether-beta-cyclodextrin physical mixture sodium chloride

Get HCT 3012 and the sulfobutyl ether-beta-cyclodextrin physical mixture 200g adding distil water 800ml stirring and dissolving of comparative example 6 preparations, add sodium chloride 8-9g, with 0.05N hydrochloric acid and 0.05N sodium hydroxide solution, adjust pH to 5.5-6.5, supplement distilled water to 10L, add 2.5g active carbon, stir 30min.Solution takes off charcoal fill (100ml/ bottle), 115 ℃ of 30min pressure sterilizings and get final product.

test example 1hCT 3012-hydroxypropyl-beta-cyclodextrin inclusion checking (structural characterization)

A ultraviolet spectrophotometry

1. get HCT 3012 appropriate, add 50 times of volume distilled water, ultrasonic 20min, standing separatory, water layer ultraviolet determination, the results are shown in Figure 3.

2. HCT 3012 is appropriate, is mixed with methanol solution, and ultraviolet determination the results are shown in Figure 4.

3. HP-β-CD is mixed with aqueous solution in right amount, and ultraviolet determination the results are shown in Figure 5.

4. HP-β-CD is mixed with methanol solution in right amount, and ultraviolet determination the results are shown in Figure 6.

5. HCT 3012-HP-β-CD (being prepared by embodiment 14) is appropriate, is mixed with the aqueous solution containing HCT 3012 4 μ g/ml, take identical HP-β-CD aqueous solution as blank, and ultraviolet determination, the results are shown in Figure 7.

6. HCT 3012-HP-β-CD (being prepared by embodiment 14) is appropriate, is mixed with the methanol solution containing HCT 3012 4 μ g/ml, take identical HP-β-CD methanol solution as blank, and ultraviolet determination, the results are shown in Figure 8.

Interpretation of result:

HCT 3012 crude drug is fat-soluble strong, is oily, after it is mixed with water, becomes oil droplet shape to be deposited in water, moisture is gone out to rear mensuration water layer uv absorption and find without obvious absorption peaks (Fig. 3), illustrates that HCT 3012 dissolubility in water is very poor;

HCT 3012 has certain solubility in methanol, so its methanol solution can reflect its ultraviolet feature, and the methanol solution of HCT 3012 has absorption maximum at 232nm place as shown in Figure 4;

Fig. 7 shows that the aqueous solution of HCT 3012-HP-β-CD (clathrate) has absorption maximum at 232nm place, Fig. 8 shows that the methanol solution of HCT 3012-HP-β-CD (clathrate) has absorption maximum at 232nm place, both characteristic ultraviolet absorptions to HCT 3012 crude drug the characteristic ultraviolet absorption (Fig. 4) in methanol similar.Above-mentioned experiment conclusion explanation HCT 3012 and HP-β-CD have formed clathrate and have increased the dissolubility of HCT 3012 in water.

B infrared spectrophotometer

1. get 0.2g KBr, be pressed into sheet, drip HCT 3012 acetone soln (5%) in the above, under infrared lamp, dry, infrared analysis, the results are shown in Figure 9.

2. get 0.2g KBr, get 10mg HP-β-CD, mix and be pressed into sheet, infrared analysis, the results are shown in Figure 10.

3. get 0.2g KBr, get 10mg HCT 3012-hydroxypropyl-beta-cyclodextrin inclusion (being prepared by embodiment 14), mix and be pressed into sheet, infrared analysis, the results are shown in Figure 11.。

4. get 0.2g KBr, get 10mg HCT 3012-HP-β-CD physical mixture, mix and be pressed into sheet, infrared analysis, the results are shown in Figure 12.

Interpretation of result: infared spectrum demonstration, HCT 3012 crude drug is at 3050-2850cm ^-1, 1650-750cm ^-1there is obvious absorption peaks, at 1735cm ^-1there is strong absorption (as shown in figure 10) at place.After HCT 3012-hydroxypropyl-beta-cyclodextrin inclusion forms, former 3050-2850cm ^-1, 1650-750cm ^-1absworption peak disappears substantially, 1735cm ^-1carbonyl peak trap obviously decline, illustrate that clathrate forms (as shown in figure 12).

test example 2the structural characterization of nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug) cyclodextrin clathrate prepared by other embodiment

According to the method for test example 1, nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug) cyclodextrin clathrate prepared by other embodiment has carried out structural characterization, simultaneously, with physical mixture (preparation method of physical mixture is with reference to comparative example 4 and 5) in contrast, the results are shown in Table 1.

Table 1

Annotation: ratio of infrared absorption intensity S represents strong absorption, and M represents medium absorption, and W represents weak absorption

Conclusion: the characteristic ultraviolet absorption of the aqueous solution of the clathrate in the upper table of ultraviolet detection result demonstration is the characteristic ultraviolet absorption in methanol similar (identical maximum absorption wavelength) with crude drug, illustrates that said medicine and beta-cyclodextrin derivative have formed clathrate and increased its dissolubility in water; Infrared analysis shows that crude drug and clathrate are directly used pressing potassium bromide troche to have obvious absorption peaks, and the absworption peak that clathrate forms in rear former crude drug collection of illustrative plates all obviously declines or substantially disappears, and illustrates that clathrate forms.

test example 3hCT 3012-sulfobutyl ether-beta-cyclodextrin inclusion compound drug loading is measured

The content of HCT 3012 in rp-hplc determination clathrate:

Chromatographic condition: C18 reversed phase chromatographic column; Mobile phase A: methanol, Mobile phase B: water (containing 0.1% formic acid), isocratic elution (65:35, v/v); Detect wavelength: 232nm.

The preparation of reference substance solution: it is appropriate that precision takes HCT 3012 reference substance, dissolves and dilutes the solution product solution in contrast of preparation 0.1mg/mL by mobile phase.

The preparation of sample solution: it is appropriate that precision takes HCT 3012-sulfobutyl ether-beta-cyclodextrin inclusion compound, dissolves and dilutes by mobile phase the need testing solution that preparation is equivalent to HCT 3012 0.1mg/mL.

External standard method is calculated the content of Nai Puxinuo, brings following formula into and calculates inclusion rate and drug loading:

Amount/HCT 3012 addition * 100% that contains HCT 3012 in inclusion rate (%)=final clathrate

In drug loading (%)=final clathrate containing the amount of HCT 3012/finally obtain product volume * 100%.

Result: the drug loading of measuring as stated above embodiment 1, embodiment 13 and embodiment 18 the results are shown in Table 2.

test example 4hCT 3012-hydroxypropyl-beta-cyclodextrin inclusion drug loading is measured

The content of HCT 3012 in rp-hplc determination clathrate:

The preparation of sample solution: it is appropriate that precision takes HCT 3012-hydroxypropyl-beta-cyclodextrin inclusion (being prepared by embodiment 3), dissolves and dilutes by mobile phase the need testing solution that preparation is equivalent to HCT 3012 0.1mg/mL.

Result: the drug loading of measuring as stated above embodiment 8, embodiment 14 and embodiment 15 the results are shown in Table 2.

Nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug) beta-schardinger dextrin-and the derivative clathrate drug loading thereof that with reference to the method for test example 3 and 4, can measure other all embodiment and comparative example, the results are shown in Table 2

Table 2

Conclusion:

(1) comparative example 1-4 is general water saturation solwution method, polishing, and clathrate inclusion rate and the drug loading of these method gained are all too low, cannot be applicable to pharmaceutical preparation, and does not realize the not recovery of enclose crude drug.

(2) the nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug)-beta-cyclodextrin derivative clathrate of embodiment 1-21 for preparing by this patent method, compare with comparative example, this patent method is easy and simple to handle, drug loading and inclusion rate significantly improve, be applicable to the requirement of industrialization preparation completely, and realized the not recovery of enclose crude drug, be conducive to reduce costs.

(3) inclusion rate that embodiment adds enclose auxiliary agent reaches more than 70%, drug loading is more than 5%, higher than the experiment embodiment that does not add enclose auxiliary agent, so enclose auxiliary agent is more conducive to the raising of clathrate inclusion rate and drug loading, and preparation technology preferably adds enclose auxiliary agent method.

test example 5hCT 3012-hydroxypropyl-beta-cyclodextrin inclusion Bioavailability Determination

HCT 3012-hydroxypropyl-beta-cyclodextrin inclusion to embodiment 15 preparations carries out Evaluation On The Bioavailability.

The gavage liquid of preparing HCT 3012 raw material and HCT 3012-hydroxypropyl-beta-cyclodextrin inclusion, successively (7 days, interval) is oral gives 6 beasle dogs, LC-MS/MS method is measured respectively difference and is got the HCT 3012 of blood point and the blood drug level of major metabolite naproxen thereof, draw drug-time curve (Figure 13,14), relatively medicine moves parameter, and the pharmacokinetic parameter of HCT 3012 and HCT 3012-hydroxypropyl-beta-cyclodextrin inclusion is referring to table 3.

Sample pretreatment: accurate absorption blood plasma 200 μ L to be measured, be placed in 5mL EP pipe, add 20 μ L inner mark solutions (methanol is diluted to 0.5 μ g/mL), 20 μ L methanol, 1mL ethyl acetate vortex 3min, the centrifugal 10min of 8000r/min, getting supernatant nitrogen dries up, add 100 μ L80% methanol, vortex 5min, 14000rmin ^-1centrifugal 10min, 80 μ L are in sample introduction bottle.

Chromatographic condition: C18 reversed phase chromatographic column; Mobile phase A: methanol, Mobile phase B: water (containing 0.1% formic acid), isocratic elution (72:28, v/v).

Mass spectrum condition: electric spray ion source (ESI source), positive ion mode, source temperature is 650 ℃.Source injection electric is 5.5kV, and atomization gas and heat air are respectively 60 and 65psi, and gas curtain gas is 25psi, and seam heating, adopts multiple-reaction monitoring pattern (MRM).The solution of HCT 3012, naproxen bunch voltage (DP), collision energy (CE) and monitoring ion pair are respectively: HCT 3012 40V, 15eV, 348.2/302.2, naproxen 37V, 19eV, 231.1/185.1.

Female medicine and the non-compartment model statistical moment of metabolite parameter before and after table 3 enclose

Note: physical mixture is prepared by comparative example 6

Result: with ratio before enclose,

(1) area under the AUC(drug-time curve of enclose stepmother medicine (HCT 3012) and metabolite (naproxen)) all obviously increase, illustrate that drug bioavailability increases;

The MRT(mean residence time of enclose stepmother medicine and metabolite) and t (2) _1/2(eliminating the half-life) all increases, and illustrates that medicine need to be eliminated the longer time;

(3) T of enclose stepmother medicine and metabolite _max(peak time) is constant, illustrates that medicine reaches time of maximum concentration substantially constant;

(4) enclose stepmother medicine V(apparent volume of distribution) substantially constant, metabolite obviously reduces, and illustrates that the distribution of female medicine is substantially constant, and the blood drug level of metabolite raises;

(5) the CL(clearance rate of enclose stepmother medicine and metabolite) all obviously reduce, illustrate that medicine elimination slows down;

(6) C of enclose stepmother medicine and metabolite _max(peak concentration) all significantly increases, and illustrates that the absorption of female medicine and metabolite strengthens.

Conclusion: HCT 3012-hydroxypropyl-beta-cyclodextrin inclusion bioavailability is apparently higher than HCT 3012 crude drug

test example 6hCT 3012-sulfobutyl ether-beta-cyclodextrin inclusion compound stability study

The present embodiment adopts high performance liquid chromatography to investigate the stability of the HCT 3012-sulfobutyl ether-beta-cyclodextrin inclusion compound of embodiment 1 preparation, and contrast with HCT 3012 and amylum pregelatinisatum, the sucrose physical mixture of 7 preparations of HCT 3012 crude drug and comparative example, the results are shown in Table 4, table 5.

The experiment of A long-time stability

The long-term stable experiment data of table 4 HCT 3012-sulfobutyl ether-beta-cyclodextrin inclusion compound

Long-term stable experiment result shows: HCT 3012-sulfobutyl ether-beta-cyclodextrin inclusion compound is more stable than crude drug HCT 3012 and physical mixture.

B accelerated test

The accelerated test data of table 5 HCT 3012-sulfobutyl ether-beta-cyclodextrin inclusion compound

Accelerated test result of the test shows: HCT 3012-sulfobutyl ether-beta-cyclodextrin inclusion compound is more stable than crude drug HCT 3012 and physical mixture.

Conclusion: HCT 3012-sulfobutyl ether-beta-cyclodextrin inclusion compound is stable higher than HCT 3012 raw material and its pharmaceutical adjunct mixture.

test example 7hCT 3012 and the experiment of its beta-cyclodextrin derivative clathrate preparation performance comparison

HCT 3012-the sulfobutyl ether-beta-cyclodextrin inclusion compound of embodiment 13,14 preparation of take is example, has compared the preparation performance of its HCT 3012 of preparing with crude drug and comparative example 7 and amylum pregelatinisatum, sucrose physical mixture, in Table 6.

Table 6 HCT 3012 beta-cyclodextrin derivative clathrate and HCT 3012 crude drug parameter comparison

Conclusion: HCT 3012-sulfobutyl ether-beta-cyclodextrin inclusion compound and HCT 3012-hydroxypropyl-beta-cyclodextrin inclusion water solublity are higher than crude drug HCT 3012, and aqueous solution clarity can be used for well the preparation of liquid preparation, crude drug HCT 3012 and its pharmaceutical adjunct physical mixture occur significantly muddy in configuration aqueous solution process, through the long period, place and be found to be crude drug oil droplet, be therefore unsuitable for making liquid preparation.

embodiment 22hCT 3012-sulfobutyl ether-beta-cyclodextrin inclusion compound is prepared tablet

HCT 3012-sulfobutyl ether-beta-cyclodextrin inclusion compound (drug loading 6.85%) 100g that gets embodiment 1 preparation, adds amylum pregelatinisatum 100g, sucrose 25g, and magnesium stearate 2.5g, mix homogeneously, direct powder compression, makes 500, film coating.

embodiment 23hCT 3012 and sulfobutyl ether-beta-cyclodextrin thing physical mixture are prepared tablet

The HCT 3012 and the sulfobutyl ether-beta-cyclodextrin physical mixture 90g that get comparative example 6 preparations, add amylum pregelatinisatum 110g, sucrose 25g, and magnesium stearate 2.5g, mix homogeneously, direct powder compression, makes 500, film coating.

embodiment 24the transfusion of HCT 3012-sulfobutyl ether-beta-cyclodextrin inclusion compound sodium chloride

A sodium chloride transfusion preparation technology

Get HCT 3012-sulfobutyl ether-beta-cyclodextrin 250g(drug loading 4.19% of embodiment 13 preparations) adding distil water 1000ml stirring and dissolving, add sodium chloride 9-10g, with 0.05N hydrochloric acid and 0.05N sodium hydroxide solution, adjust pH to 5.5-6.5, supplement distilled water to 10L, add 2.5g active carbon, stir 30min.Solution takes off charcoal fill (100ml/ bottle), 115 ℃ of 30min pressure sterilizings and get final product.

B vascular stimulation test

Get 8 of rabbit and be divided into two groups of experimental group and matched groups, experimental group, by the rabbit auricular vein above-mentioned sodium chloride transfusion 40ml that slowly instils, drips fast 1.5ml/min, successive administration 3 days; Matched group gives 10% glacial acetic acid, at the negative contrast of 0.9% sodium chloride transfusion injection of instiling of the offside rabbit ear, successive administration 3 days.

Result: test group successive administration 3 days, local no abnormality seen, with the same to side injection 0.9% sodium chloride injection, and inject visible contrafluxion, thickening after 10% glacial acetic acid, oozes out.Show that clathrate of the present invention is little to the blood vessel irritation of animal, be suitable for this clathrate to be prepared into injection-type.

C hemolytic test

Method: one of new zealand rabbit, get blood 10ml, prepare according to a conventional method blood cell, and with normal saline dilution, become 2% suspension for test.

Criterion: full haemolysis (the clear and bright redness of solution, the acellular residual fraction in the pipe end); Haemolysis (the clear and bright redness of solution or brown, the pipe end has a small amount of erythrocyte residual); Without haemolysis (erythrocyte all sinks, supernatant liquid achromatism and clarity); Assemble (though erythrocyte aggregation appears in haemolysis not, after jolting, can not disperse).

Result: blood cell in the transfusion of above-mentioned HCT 3012-sulfobutyl ether-beta-cyclodextrin inclusion compound sodium chloride, 37 ℃ of insulation 3h of water-bath,, there is not coagulation in haemolysis yet.

D toxicity test

Method: get 10 of healthy mices, male and female dual-purpose, body weight 18～22g, above-mentioned sodium chloride transfusion is through mouse tail vein injection this product 0.5ml.

Result: in 48h, have no dead and any poisoning symptom phenomenon.

E hypersensitive test

Method: 18 of extracting waste Cavia porcelluss, body weight 280～350g, male and female half and half.Be divided into three groups (transfusion of HCT 3012-sulfobutyl ether-beta-cyclodextrin inclusion compound sodium chloride, normal saline and egg protein liquid groups), 6 every group, test according to a conventional method.

Result: Cavia porcellus is being injected latter 14 days and 21 days first, the transfusion of HCT 3012-sulfobutyl ether-beta-cyclodextrin inclusion compound sodium chloride and normal saline matched group are without anaphylaxis, positive control egg protein group has anaphylaxis, shows that the transfusion of HCT 3012-sulfobutyl ether-beta-cyclodextrin inclusion compound sodium chloride can not cause Cavia porcellus anaphylaxis.

embodiment 25hCT 3012-sulfobutyl ether-beta-cyclodextrin inclusion compound glucose infusion liquid

A glucose infusion liquid preparation technology

Get glucose for injection 500g, injecting blunges is dissolved to 1000ml, adds 1g active carbon, heats micro-15min of boiling, de-charcoal.Get HCT 3012-sulfobutyl ether-beta-cyclodextrin 250g(drug loading 6.85% of embodiment 1 preparation) after adding distil water 1000ml stirring and dissolving, pour in Glucose Liquid, stir, moisturizing, to 8L, is adjusted pH to 4.5-5.5 with 0.05N hydrochloric acid and 0.05N sodium hydroxide solution, and moisturizing is to 10L, stir 20min, use respectively filter and sand stick to carry out coarse filtration and fine straining, fill (100ml/ bottle), 115 ℃ of 30min pressure sterilizings and get final product.

B vascular stimulation test

Method: get 8 of rabbit and be divided into two groups of experimental group and matched groups, experimental group, by the rabbit auricular vein above-mentioned glucose infusion liquid 40ml that slowly instils, drips fast 1.5ml/min, successive administration 3 days; Matched group gives 10% glacial acetic acid, at the negative contrast of 5% glucose injection of instiling of the offside rabbit ear, successive administration 3 days.

Result: test group successive administration 3 days, local no abnormality seen, with the same to side injection 5% glucose injection, and inject visible contrafluxion, thickening after 10% glacial acetic acid, oozes out.Show that clathrate of the present invention is little to the blood vessel irritation of animal, be suitable for this clathrate to be prepared into injection-type.

C hemolytic test

Result: blood cell is 37 ℃ of insulation 3h of water-bath in above-mentioned glucose infusion liquid, and haemolysis, coagulation does not occur yet.

D toxicity test

Method: get 10 of healthy mices, male and female dual-purpose, body weight 18～22g, above-mentioned glucose infusion liquid is through mouse tail vein injection this product 0.5ml.

Result: in 48h, have no dead and any poisoning symptom phenomenon.

E hypersensitive test

Method: 18 of extracting waste Cavia porcelluss, body weight 280～350g, male and female half and half.Be divided into three groups (HCT 3012-sulfobutyl ether-beta-cyclodextrin inclusion compound glucose infusion liquid, normal saline and egg protein liquid groups), 6 every group, test according to a conventional method.

Result: Cavia porcellus is being injected latter 14 days and 21 days first, HCT 3012-sulfobutyl ether-beta-cyclodextrin inclusion compound glucose infusion liquid and normal saline matched group are without anaphylaxis, positive control egg protein group has anaphylaxis, shows that HCT 3012-sulfobutyl ether-beta-cyclodextrin inclusion compound glucose infusion liquid can not cause Cavia porcellus anaphylaxis.

test example 8transfusion stabilization Journal of Sex Research

HCT 3012 with comparative example 8 preparations is infused as contrasting with sulfobutyl ether-beta-cyclodextrin physical mixture, investigated HCT 3012-sulfobutyl ether-beta-cyclodextrin inclusion compound glucose infusion liquid room temperature long-time stability of lower 12 months of embodiment 25 preparations, and 12 months accelerated stabilities.The results are shown in Table 7.

Table 7 long-term stable experiment data

Table 8 accelerated test data

Conclusion: transfusion stabilization Journal of Sex Research shows: HCT 3012-sulfobutyl ether-beta-cyclodextrin inclusion compound transfusion stabilization is good, in long-term stable experiment data and accelerated test, there is not the phenomenons such as muddiness, emulsifying in prolongation outward appearance clarification in time.Transfusion purity changes little, meets quality standard (purity >=99%).HCT 3012 and the transfusion of sulfobutyl ether-beta-cyclodextrin physical mixture, in long-term stable experiment data and accelerated test, prolongation outward appearance in time occurs muddy to emulsifying, and purity declines fast, its poor stability is described, effective ingredient degraded is fast, is unsuitable for developing liquid preparation.

test example 9tablet quality research

Investigate respectively the correlated performance parameter of tablets of embodiment 22 and 23 preparations, the results are shown in Table 9 and table 10.

The accumulation stripping percentage rate of two kinds of tablets of table 9

Table 10 uniformity and related substance testing result

Sample	Moisture (n=3)	Uniformity of dosage units (n=10)	Content/labelled amount %(n=4)	Related substance %(n=2)
					Embodiment 22	3.18±0.01	4.58	99.0±0.4	0.08±0.0
Embodiment 23	6.18±0.01	17.12	93.5±18.2	1.08±0.0

Conclusion: tablet quality research shows, tablet prepared by HCT 3012-sulfobutyl ether-beta-cyclodextrin inclusion compound is at the oral tablet of all preparing higher than physical mixture aspect stripping percentage rate, moisture, uniformity of dosage units, content/labelled amount % and related substance %.

Tablet accumulation stripping percentage rate prepared by physical mixture is too low, cause bioavailability low, do not meet preparation requirement, and its oral tablet uniformity of preparing is poor, this and crude drug viscosity are large, in pharmaceutical adjunct, cannot mix relevantly completely, therefore, HCT 3012-sulfobutyl ether-beta-cyclodextrin inclusion compound is more suitable for the preparation of oral tablet.

Specific description of embodiments of the present invention above does not limit the present invention, and those skilled in the art can make according to the present invention various changes or distortion, only otherwise depart from spirit of the present invention, all should belong to the scope of claims of the present invention.

Claims

1. nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug) beta-schardinger dextrin-or derivatives thereof clathrate, it is characterized in that, contain nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug) and beta-schardinger dextrin-or beta-cyclodextrin derivative, the mol ratio of nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug) and beta-schardinger dextrin-or beta-cyclodextrin derivative is 1:1～1:25.

2. nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug) beta-schardinger dextrin-or derivatives thereof clathrate according to claim 1, it is characterized in that, the mol ratio of described nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug) and described beta-schardinger dextrin-or beta-cyclodextrin derivative is 1:1～1:10.

3. nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug) beta-schardinger dextrin-or derivatives thereof clathrate according to claim 1 and 2, it is characterized in that, described nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug) beta-schardinger dextrin-or derivatives thereof clathrate Subjective and Objective molecular proportion is 1:2 or 1:1.

4. according to the nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug) beta-schardinger dextrin-or derivatives thereof clathrate described in any one in claims 1 to 3, it is characterized in that, described nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug) is selected from a kind of in the compound with following general structure:

Wherein, X is-(CH ₂) _n1-Z-(CH ₂) _n2-, n wherein ₁, n ₂be selected from independently of one another 0,1,2,3,4 or 5;

5. according to the nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug) beta-schardinger dextrin-or derivatives thereof clathrate described in any one in claim 1 to 4, it is characterized in that, described nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug) is selected from HCT 3012,2-(acetoxyl group) benzoic acid-3-(nitroxymethyl) phenyl ester, 2-(acetoxyl group) benzoic acid-4-(nitroxymethyl) phenyl ester, 2-(acetoxyl group) benzoic acid-2-(nitroxymethyl) phenyl ester or 2-(acetoxyl group) benzoic acid-2-(2-nitrooxy ethyoxyl) ethyl ester; Be preferably HCT 3012.

6. according to the nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug) beta-schardinger dextrin-or derivatives thereof clathrate described in any one in claim 1 to 5, it is characterized in that, described beta-cyclodextrin derivative is selected from HP-β-CD, sulfobutyl ether-beta-cyclodextrin, hydroxyethyl-β-cyclodextrin, dihydroxypropyl-beta-schardinger dextrin-, first group-beta-cyclodextrin, carboxymethyl-beta-cyclodextrin; Be preferably HP-β-CD or sulfobutyl ether-beta-cyclodextrin.

7. a method of preparing the nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug) beta-schardinger dextrin-or derivatives thereof clathrate described in any one in claim 1 to 6, comprising:

8. preparation method according to claim 7, it is characterized in that, described quaternary ammonium enclose auxiliary agent is selected from one or more in tetrabutyl ammonium bromide, cetyl trimethyl ammonium bromide, benzyltriethylammoinium chloride or benzyl tributyl ammonium chloride, is preferably tetrabutyl ammonium bromide or benzyltriethylammoinium chloride;

It is (C that described crown ether-like enclose auxiliary agent is selected from general formula ₂h ₄o-) _ncompound, wherein, the natural number that n is 1-6; Be preferably one or more in 15-crown ether-5, hexaoxacyclooctadecane-6-6,12-crown ether-4, dicyclohexyl hexaoxacyclooctadecane-6-6 or dibenzo hexaoxacyclooctadecane-6-6;

Described polyethylene glycols enclose auxiliary agent is selected from one or more in PEG-400, PEG-600, PEG-1000, PEG-1500, PEG-4000 or PEG-6000; Be preferably PEG-400 and PEG-6000.

9. according to the preparation method described in claim 7 or 8, it is characterized in that, described enclose auxiliary agent use amount is the 0.1%-10% of described nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug) quality, is preferably 0.1-5%.

10. according to arbitrary described preparation method in claim 7 to 9, it is characterized in that, the not miscible organic solvent of described and water is selected from ethyl acetate, methyl acetate, isopropyl acetate, butyl acetate, dichloromethane, 1,2-dichloroethanes, toluene, benzene, petroleum ether, normal hexane; Be preferably ethyl acetate or dichloromethane;

11. according to the preparation method described in any one in claim 7 to 9, it is characterized in that, described and organic solvent water immiscible phase is selected from methanol, ethanol, isopropyl alcohol, acetone, propylene glycol, ethylene glycol and glycerol; Be preferably ethanol, isopropyl alcohol and glycerol;

12. according to the preparation method described in any one in claim 7 to 10, it is characterized in that, specifically comprises the steps:

(3) after two kinds of solution that above-mentioned steps 1 and 2 obtained mix, add described nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug) quality 0.1%-10%, be preferably the described enclose auxiliary agent of 0.1-5%, vigorous stirring, ultrasonic or grinding 10-60min;

13. according to the preparation method described in any one in claim 7,8,9 or 11, it is characterized in that, specifically comprises the steps:

14. according to the preparation method described in any one in claim 7 to 9, it is characterized in that, specifically comprises the steps:

15. 1 kinds of methods of preparing the nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug) beta-schardinger dextrin-or derivatives thereof clathrate described in any one in claim 1 to 6, specifically comprise the steps:

(3) two kinds of solution that above-mentioned steps 1 and 2 obtained mix, vigorous stirring, ultrasonic or grinding 10-60min;

16. 1 kinds of methods of preparing the nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug) beta-schardinger dextrin-or derivatives thereof clathrate described in any one in claim 1 to 6, specifically comprise the steps:

17. 1 kinds of methods of preparing the nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug) beta-schardinger dextrin-or derivatives thereof clathrate described in any one in claim 1 to 6, specifically comprise the steps:

(1) get nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug) described in oily, add the distilled water of 1～25 times of quality and beta-schardinger dextrin-or the beta-cyclodextrin derivative of 1～25 times of mole, vigorous stirring, ultrasonic or grind 10～60min;

18. 1 kinds of methods of preparing the nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug) beta-schardinger dextrin-or derivatives thereof clathrate described in any one in claim 1 to 6, specifically comprise the steps:

(2) add 10～350 times of mole distilled water, stir 10～30min;

(3) by step 2 gained solution left standstill 20～40min, separatory, directly separated also recovery is not by the nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug) of enclose;

19. 1 kinds of methods of preparing the nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug) beta-schardinger dextrin-or derivatives thereof clathrate described in any one in claim 1 to 6, specifically comprise the steps:

20. 1 kinds of pharmaceutical compositions, this pharmaceutical composition comprises nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug) beta-schardinger dextrin-or derivatives thereof clathrate and the pharmacy adjuvant described in any one in claim 1 to 6.

21. pharmaceutical compositions according to claim 20, is characterized in that, described pharmaceutical composition is injection or oral formulations; Preferably, described injection is transfusion, liquid drugs injection or powder injection formulation; Described oral formulations is oral liquid, syrup, tablet, capsule or granule; Described pharmacy adjuvant is selected from one or more in amylum pregelatinisatum, magnesium stearate, lactose, sucrose, glucose, sodium chloride, water and sorbitol.

Nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug) beta-schardinger dextrin-or derivatives thereof clathrate in 22. claim 1 to 6 described in any one and the pharmaceutical composition described in claim 18 or 19 purposes in preparation treatment diseases associated with inflammation; Described diseases associated with inflammation comprises rheumatic arthritis, rheumatoid arthritis and osteoarthritis.