CN101385739A - Medicine composition for improving the absorption of the anion polysaccharide - Google Patents
Medicine composition for improving the absorption of the anion polysaccharide Download PDFInfo
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- CN101385739A CN101385739A CNA200810155946XA CN200810155946A CN101385739A CN 101385739 A CN101385739 A CN 101385739A CN A200810155946X A CNA200810155946X A CN A200810155946XA CN 200810155946 A CN200810155946 A CN 200810155946A CN 101385739 A CN101385739 A CN 101385739A
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Abstract
The invention discloses a pharmaceutical composition for improving the absorption of anionic polysaccharides, and the pharmaceutical composition can promote the absorption of drug delivery of the anionic polysaccharides through alkaline amino acids.
Description
Technical field:
The invention belongs to field of pharmaceutical preparations, exactly it is a kind of pharmaceutical composition that anion polysaccharide absorbs that improves.
Background technology:
The anion polysaccharide molecular weight is bigger, water solublity is better, generally belongs to the III type of biopharmaceutics categorizing system, promptly belongs to the medicine of highly dissoluble and low permeability, therefore the various absorption barriers that are difficult to effectively be difficult to through human body enter blood circulation, generally are drug administration by injection.
(low molecular weight heparin is unfraction heparin through chemistry or enzyme process depolymerization and gets LMWH) that relative molecular mass is 4000～6500 to Low molecular heparin.Compare with unfraction heparin that to have an anti thrombotic action strong, hemorrhage side effect is little, the bioavailability height, and long half time is with characteristics such as plasma protein and platelet combination rate be low.Can be used for preventing and treating Orthopeadic Surgery postoperative venous thrombosis, acute myocardial infarction, unstable angina pectoris and be used for hemodialysis, extracorporeal circulation etc.Low molecular heparin is because other administration absorbs difficulty, and it is clinical to have only injection to be used at present.But be used for prevention and treat thrombosis needing long term administration, this uses to the patient and makes troubles.Administration for convenience, enlarge LMWH in Clinical Application, researcheres are devoted to the research of novel form of administration and approach always, as (Zhao Jun, Wang Juan, Zhai Guangxi such as bio-adhesive preparation, micro-nano preparation, aerosol inhalant, sublingual lozenge, rectal suppository, nasal drop, the progress of Low molecular heparin preparation [J], food and medicine, 2006,8 (06): 10～12).Patent (200710010558.8, complex and preparation and preparation method that chitosan and derivant thereof and Low molecular heparin form) has been introduced the method by chitosan and derivant and the absorption of Low molecular heparin formation complex promotion Low molecular heparin.But owing to reasons such as safety, stability, individual variation, bioavailability, LMWH is ejection preparation listing nothing but still at present.
Summary of the invention:
The object of the present invention is to provide a kind of new pharmaceutical composition that anion polysaccharide absorbs that improves, making with the Low molecular heparin by this compositions is that the non-injection administration of the anion polysaccharide of representative becomes possibility.
Be general in the former pharmaceutical preparation of the basic amino acid of representative with the arginine as amino acid supplements, pH regulator agent.In the present invention, after we utilize salifies such as a large amount of acid group of anion polysaccharide and arginine, utilize the structural a large amount of guanidine radicals of double salt or aminoly promote anion polysaccharide to see through to absorb barrier to enter blood circulation, increase bioavailability.The detailed description of the invention is as follows:
Improve the pharmaceutical composition that anion polysaccharide absorbs, it is characterized in that it comprises
(a) anion polysaccharide;
(b) basic amino acid.
Anion polysaccharide is to well known to a person skilled in the art notion, and present known anion polysaccharide is all within protection scope of the present invention.The claimed anion polysaccharide of the present invention comprises one or more of following material: Low molecular heparin; low molecular sodium heparin; low molecular heparin calcium; heparin; chondroitin sulfate; the oligomerization hyaluronic acid; low molecular weight hyaluronic acid; hyaluronic acid; the oligomerization hyaluronate sodium; low-numerator sodium hyaluronate; hyaluronate sodium; alginic acid; low molecule alginic acid; the sulphation pachyman; dermatan sulfate; people's keratan sulfate; chondroitin sulfate A; dextran sulfate; kelp polysaccharide sulfate; fucoidin; sulfated galactan; carrageenin; alginic acid; the Radix Ginseng Rubra acidic polysaccharose; pine nuts of Korean pine shell acidic polysaccharose; the Fructus Jujubae acidic polysaccharose; the spirulina acidic polysaccharose; the Radix Aconiti Lateralis Preparata acidic polysaccharose; the microcystic aeruginosa acidic polysaccharose; the Tremella acidic polysaccharose; the Stichopus japonicus acidic polysaccharose; Aloe polysaccharide; Radix Morinae Bulleyanae and Stichopus japonicus acid mucopolysaccharide; sialic acid; the sulphation dextran; the sulphation lentinan; the sulphation xylan; polygalacturonic acid; polymannuronate; polyglucuronic acid; various controlling sulfate polyoses, or the salt of above-mentioned substance and derivant.Anion polysaccharide of the present invention is preferably selected from one or more in the following material: Low molecular heparin, low molecular sodium heparin, low molecular heparin calcium, oligomerization hyaluronic acid, low molecular weight hyaluronic acid, oligomerization hyaluronate sodium, low-numerator sodium hyaluronate, or the salt of above-mentioned substance and derivant.Anion polysaccharide of the present invention is Low molecular heparin or its salt and derivant more preferably.
Improve the pharmaceutical composition that anion polysaccharide absorbs, it is characterized in that wherein said basic amino acid is selected from one or more in the following material: the mixture of arginine, lysine and their various organic or inorganic salt, various isomer, various mixture of isomers, various organic or inorganic salt.
Improve the pharmaceutical composition that anion polysaccharide absorbs, it is characterized in that wherein said basic amino acid combines or physical mixed with ionic means with anion polysaccharide, or physical mixed, ionic means are in conjunction with coexistence; Preferably with ionic means in conjunction with or physical mixed, ionic means in conjunction with coexistence.Basic amino acid has the effect of anion polysaccharide absorption enhancer in the present invention.
The pharmaceutical composition that improves the anion polysaccharide absorption of the present invention, wherein the mass ratio of basic amino acid and anion polysaccharide is 1:100～1000:1, is preferably 1:1～100:1.
Neutral and alkali aminoacid of the present invention and anion polysaccharide are dissolving or after dissolving this solution carried out drying and the dry thing that obtains in the solvent that basic amino acid and anion polysaccharide are allowed on pharmacopedics with the bonded implementation method of ionic means.The salt of anion polysaccharide and basic amino acid are that the dissolving back adds an amount of acid in the solvent that allows on pharmacopedics of the salt with anion polysaccharide with the bonded implementation method of ionic means among the present invention, and then the adding basic amino acid, dissolving or after dissolving, this solution carried out drying and the dry thing that obtains.Drying means comprises any drying means well known by persons skilled in the art, comprises one or more of following material: spray drying, lyophilization, vacuum drying, fluidized drying, infrared drying.
The pharmaceutical composition that improves the anion polysaccharide absorption that the present invention protected can also comprise other medicinal ingredient arbitrarily well known by persons skilled in the art such as microcrystalline Cellulose, enteric-coating material, intestinal pasting material etc. except basic amino acid of the present invention and anion polysaccharide.Except basic amino acid as the absorption enhancer, the pharmaceutical composition that improves the anion polysaccharide absorption of the present invention can no longer contain other absorption enhancer, also can contain other absorption enhancer, other absorption enhancer comprises one or more of (but being not limited only to) following material: the salt of cholic acid and derivant thereof, the carbomer class, the chitosan class, the Sargassum acids, Tweens, the poloxamer class, fatty acid, fatty acid salt, Capric acid sodium salt, sodium caprylate, enuatrol, linoleic acid sodium, sodium lauryl sulphate, the salt of EDTA, cyclodextrin, the polyoxyethylene fatty acid ester class, the polyoxyethylene aliphatic alcohol ether class, C
8-C
18The monoglyceride of fatty acid, C
8-C
18Two glyceride of fatty acid, C
8-C
18The triglyceride of fatty acid, lipid, non-ionic surface active agent, salt, mixture and the derivant of wearing film peptide, glyceryl monostearate (Gelucire), Tween 80, capric acid, sad, oleic acid, linoleic acid, Palmic acid, stearic acid, medium chain triglyceride, capmuls, solid glyceride or above-mentioned substance.
The salt of cholic acid and derivant thereof comprises one or more of (but being not limited only to) following material in other absorption enhancer of the present invention: cholic acid; deoxycholic acid; dehydrocholic acid; chenodeoxycholic acid; ursodesoxycholic acid; Hyodeoxycholic Acid; lithocholic acid; glycocholic acid; taurocholic acid; glycochenodeoxycholate; cattle sulphur chenodeoxy cholic acid; sweet ammonia deoxycholic acid; taurodeoxycholic acid; sweet ammonia Hyodeoxycholic Acid; cattle sulphur Hyodeoxycholic Acid; sweet ammonia ursodesoxycholic acid; tauroursodeoxycholic acid; sweet ammonia lithocholic acid; all contain the various organic and inorganic salt of the acid of steroidal structure taurolithocholic acids etc.
Poly yamanashi esters comprises one or more of (but being not limited only to) following material in other absorption enhancer of the present invention: polyoxyethylene sorbitan monolaurate, polyethenoxy sorbitan monopalmitate, polyethenoxy sorbitan monostearate, polyoxyethylene sorbitan monooleate dehydration, polyethenoxy sorbitan list trioleate etc.
The route of administration of the pharmaceutical composition that improves the anion polysaccharide absorption that the present invention protected comprises any route of administration well known by persons skilled in the art or route of administration combination; preferred oral administration, oral administration, pulmonary administration, transdermal administration, nasal-cavity administration, preferred enteric administration in the oral administration system.
The invention has the advantages that guanidine radicals or the amino absorption that promotes anion polysaccharide by basic amino acid, safety is very good, and preparation of pharmaceutical compositions technology of the present invention is simple, quality controllable, cost is low.
Useful achievement of the present invention is that our discovery basic amino acid surprised in experiment can improve the absorption of Low molecular heparin oral administration greatly, making with the Low molecular heparin is that the non-injection administration of the anion polysaccharide of representative becomes possibility, and experimental results show that if cooperate other safe absorption enhancer such as glyceryl monostearate can further improve with the Low molecular heparin be the oral absorption of the anion polysaccharide of representative.
The specific embodiment
Illustrate concrete preparation method of the present invention by following example, but protection scope of the present invention is not limited to this.
Embodiment 1
Prescription: Low molecular heparin 1g
Arginine 3g
Preparation technology: the arginine of recipe quantity, Low molecular heparin (molecular weight is about 5000, and it is 100 ius that the anti-Xa factor of 1mg is tired, down with) are dissolved in the 100mL water, and spray drying is packed conventional capsule into promptly.
Embodiment 2
Prescription: Low molecular heparin 1g
Arginase 12 g
Mannitol 2g
Sucrose 5g
Lactose 2g
Preparation technology: arginine, the Low molecular heparin of recipe quantity are dissolved in the 100mL water, and spray drying is pressed into sublingual lozenge promptly with other adjuvant in the prescription.
Embodiment 3
Prescription: Low molecular heparin 1g
Arginase 12 g
Sodium deoxycholate 0.1g
Tween 80 0.1g
Microcrystalline Cellulose 10g
Preparation technology: arginine, the Low molecular heparin of recipe quantity are dissolved in the 100mL water, and spray drying with sodium deoxycholate, Tween 80, microcrystalline Cellulose mixing, is packed enteric coated capsule into promptly.
Embodiment 4
Prescription: Low molecular heparin 1g
Arginase 12 g
Sodium deoxycholate 0.1g
Preparation technology: arginine, the Low molecular heparin of recipe quantity are dissolved in the 100mL water, and spray drying with the sodium deoxycholate mixing, is packed enteric coated capsule into promptly.
Embodiment 5
Prescription: Low molecular heparin 1g
Arginase 12 g
Mannitol 10g
Preparation technology: arginine, Low molecular heparin, the mannitol of recipe quantity are dissolved in the 100mL water spray drying, the special-purpose capsule of the Foradil Aerolizer formoterol fumarate of packing into, the Foradil Aerolizer formoterol fumarate of the sub-heparin that promptly makes low score.
Embodiment 6
Prescription: Low molecular heparin 1g
Arginase 12 g
S—40 100g
Preparation technology: arginine, Low molecular heparin, the mannitol of recipe quantity are dissolved in the 100mL water, and spray drying is ground evenly with the S that melts in the water-bath-40, and promptly the make low score suppository of sub-heparin of mould is irritated in insulation.
Embodiment 7
Prescription: low molecular sodium heparin 1g
Arginine 3g
Dilute hydrochloric acid is an amount of
Preparation technology: with the low molecular sodium heparin (molecular weight about 5200 of recipe quantity, it is 87 ius that the anti-Xa factor of 1mg is tired) be dissolved in the 50mL water, regulate pH to 2.0 with dilute hydrochloric acid, add the arginine of recipe quantity, spray drying is packed enteric or conventional capsule into promptly.
Embodiment 8
Prescription: Low molecular heparin 1g
Arginase 12 g
Preparation technology: arginine, the Low molecular heparin of recipe quantity are dissolved in the 100mL water, and spray drying is packed enteric coated capsule into promptly.
Embodiment 9
Prescription: Low molecular heparin 1g
Arginase 12 g
Glyceryl monostearate 0.5g
Lactose 5g
Preparation technology: arginine, the Low molecular heparin of recipe quantity are dissolved in the 100mL water, and spray drying is ground with glyceryl monostearate, lactose, and mix homogeneously is packed enteric coated capsule into promptly.
Embodiment 10
Prescription: Low molecular heparin 1g
Lysine 2g
Preparation technology: lysine, the Low molecular heparin of recipe quantity are dissolved in the 100mL water, and spray drying is packed enteric coated capsule into promptly.
[test of rabbit oral absorption]
Get 30 of rabbit, 1 week of normal diet; Be divided into 5 groups at random, fasting 12h before the experiment freely drinks water.The enteric coated capsule that I number group gives only to contain Low molecular heparin (is directly packed Low molecular heparin into enteric coated capsule promptly, dosage: 1000 ius/kg); II number group contains the Low molecular heparin enteric coated capsule of glyceryl monostearate, and (1g Low molecular heparin, 0.5g glyceryl monostearate, 5g lactose are ground, and mix homogeneously is packed enteric coated capsule into promptly, dosage: 1000 ius/kg); III number group gives the (dosage: 1000 ius/kg) of the Low molecular heparin enteric coated capsule by embodiment 8 preparation; IV number group gives the (dosage: 1000 ius/kg) of the Low molecular heparin enteric coated capsule by embodiment 9 preparation; V number group gives the (dosage: 1000 ius/kg) of the Low molecular heparin enteric coated capsule by embodiment 10 preparation.Respectively at after the medication 0,1,3,5,8h gets blood 1mL in the rabbit auricular vein, injects the centrifuge tube that has added 3.8% sodium citrate 0.1mL, the centrifugal 15min of 3000r/min, separated plasma.3 in test tube with the about 8mm of internal diameter is got blood plasma 0.1mL respectively, puts in (37 ± 0.5 ℃) water bath with thermostatic control and is incubated 5min, adds 0.025mol/L calcium chloride 0.1mL respectively, and stopwatch is measured from adding calcium chloride to time that fibrin is separated out; The meansigma methods of getting 3 test tubes is the blood coagulation time of respectively getting the blood time.Calculate blood coagulation time with the difference of (0h) blood coagulation time before each period and the medication after the medication and prolong percentage rate.
The results are shown in Table 1:
Table 1: the different time blood coagulation time prolongs percentage rate after the rabbit medication
Compare with its 0h after the medication of I number group, the rat blood setting time has the trend of increase, but not statistically significant; Each time rat blood setting time significant prolongation (P＜0.05) after the medication of II number group; III number group, IV number group, V number are organized also significant prolongation (P＜0.01) of each time rat blood setting time; Time expand: IV number group〉III number group〉V number group〉II number group.Illustrate that arginine and lysine can significantly improve the absorption of Low molecular heparin oral administration, and if cooperate glyceryl monostearate can further improve the oral absorption of Low molecular heparin.
Claims (10)
1. improve the pharmaceutical composition that anion polysaccharide absorbs, it is characterized in that it comprises (a) anion polysaccharide; (b) basic amino acid.
2. pharmaceutical composition according to claim 1, it is characterized in that, wherein said anion polysaccharide comprises one or more of following material: Low molecular heparin, low molecular sodium heparin, low molecular heparin calcium, heparin, chondroitin sulfate, the oligomerization hyaluronic acid, low molecular weight hyaluronic acid, hyaluronic acid, the oligomerization hyaluronate sodium, low-numerator sodium hyaluronate, hyaluronate sodium, alginic acid, low molecule alginic acid, the sulphation pachyman, dermatan sulfate, people's keratan sulfate, chondroitin sulfate A, dextran sulfate, kelp polysaccharide sulfate, fucoidin, sulfated galactan, carrageenin, alginic acid, the Radix Ginseng Rubra acidic polysaccharose, pine nuts of Korean pine shell acidic polysaccharose, the Fructus Jujubae acidic polysaccharose, the spirulina acidic polysaccharose, the Radix Aconiti Lateralis Preparata acidic polysaccharose, the microcystic aeruginosa acidic polysaccharose, the Tremella acidic polysaccharose, the Stichopus japonicus acidic polysaccharose, Aloe polysaccharide, Radix Morinae Bulleyanae and Stichopus japonicus acid mucopolysaccharide, sialic acid, the sulphation dextran, the sulphation lentinan, the sulphation xylan, polygalacturonic acid, polymannuronate, the salt of polyglucuronic acid or above-mentioned substance and derivant.
3. pharmaceutical composition according to claim 2, it is characterized in that, wherein said anion polysaccharide is one or more in the following material: Low molecular heparin, low molecular sodium heparin, low molecular heparin calcium, oligomerization hyaluronic acid, low molecular weight hyaluronic acid, oligomerization hyaluronate sodium, low-numerator sodium hyaluronate, or the salt of above-mentioned substance and derivant.
4. pharmaceutical composition according to claim 3 is characterized in that, wherein said anion polysaccharide is Low molecular heparin or its salt and derivant.
5. pharmaceutical composition according to claim 1, it is characterized in that wherein said basic amino acid is selected from one or more in the following material: the mixture of arginine, lysine and their various organic or inorganic salt, various isomer, various mixture of isomers, various organic or inorganic salt.
6. pharmaceutical composition according to claim 1 is characterized in that, wherein said basic amino acid combines or physical mixed with ionic means with anion polysaccharide, or physical mixed, ionic means are in conjunction with coexistence.
7. pharmaceutical composition according to claim 6 is characterized in that, wherein said basic amino acid combines with ionic means with anion polysaccharide or physical mixed, ionic means in conjunction with coexistence.
8. pharmaceutical composition according to claim 1 is characterized in that wherein said basic amino acid has the effect of anion polysaccharide absorption enhancer.
9. pharmaceutical composition according to claim 1 is characterized in that, it can not comprise other outer absorption enhancer of basic amino acid, also can comprise other absorption enhancer.
10. pharmaceutical composition according to claim 3, it is characterized in that wherein said other absorption enhancer comprises one or more of following material: the salt of the salt of cholic acid and derivant thereof, carbomer class, chitosan class, Sargassum acids, Tweens, poloxamer class, fatty acid, fatty acid salt, Capric acid sodium salt, sodium caprylate, enuatrol, linoleic acid sodium, sodium lauryl sulphate, EDTA, cyclodextrin, polyoxyethylene fatty acid ester class, polyoxyethylene aliphatic alcohol ether class, C
8-C
18The monoglyceride of fatty acid, C
8-C
18Two glyceride of fatty acid, C
8-C
18The triglyceride of fatty acid, lipid, non-ionic surface active agent, salt, mixture and the derivant of wearing film peptide, glyceryl monostearate (Gelucire), Tween 80, capric acid, sad, oleic acid, linoleic acid, Palmic acid, stearic acid, medium chain triglyceride, capmuls, solid glyceride or above-mentioned substance.
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| Application Number | Priority Date | Filing Date | Title |
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| CNA200810155946XA CN101385739A (en) | 2008-10-21 | 2008-10-21 | Medicine composition for improving the absorption of the anion polysaccharide |
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| CNA200810155946XA CN101385739A (en) | 2008-10-21 | 2008-10-21 | Medicine composition for improving the absorption of the anion polysaccharide |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103719193A (en) * | 2013-12-06 | 2014-04-16 | 山东好当家海洋发展股份有限公司 | Sea cucumber brown algae nutrition cake and manufacturing method thereof |
| CN104721831A (en) * | 2015-01-28 | 2015-06-24 | 中国药科大学 | Hyaluronic acid covalently linked targeting cell-penetrating peptide and active drug containing water-soluble prodrug and preparation method thereof |
| EP2834635A4 (en) * | 2012-04-03 | 2015-09-02 | Smiths Medical Asd Inc | Heparin-bulking agent compositions and methods thereof |
| EP3110427A4 (en) * | 2014-02-24 | 2018-05-30 | Urigen Pharmaceuticals, Inc. | Compositions of pentosan polysulfate salts for oral administration and methods of use |
-
2008
- 2008-10-21 CN CNA200810155946XA patent/CN101385739A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2834635A4 (en) * | 2012-04-03 | 2015-09-02 | Smiths Medical Asd Inc | Heparin-bulking agent compositions and methods thereof |
| US9357765B2 (en) | 2012-04-03 | 2016-06-07 | Smiths Medical Asd, Inc. | Heparain-bulking agent compositions and methods thereof |
| CN103719193A (en) * | 2013-12-06 | 2014-04-16 | 山东好当家海洋发展股份有限公司 | Sea cucumber brown algae nutrition cake and manufacturing method thereof |
| EP3110427A4 (en) * | 2014-02-24 | 2018-05-30 | Urigen Pharmaceuticals, Inc. | Compositions of pentosan polysulfate salts for oral administration and methods of use |
| CN104721831A (en) * | 2015-01-28 | 2015-06-24 | 中国药科大学 | Hyaluronic acid covalently linked targeting cell-penetrating peptide and active drug containing water-soluble prodrug and preparation method thereof |
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Open date: 20090318 |