CN102100907A - Composition of oral pharmacologic active agent - Google Patents
Composition of oral pharmacologic active agent Download PDFInfo
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- CN102100907A CN102100907A CN2009102596009A CN200910259600A CN102100907A CN 102100907 A CN102100907 A CN 102100907A CN 2009102596009 A CN2009102596009 A CN 2009102596009A CN 200910259600 A CN200910259600 A CN 200910259600A CN 102100907 A CN102100907 A CN 102100907A
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Abstract
The invention relates to a composition of an oral pharmacologic active agent, a method for improving oral bioavailability and a method for treating and/or preventing diseases of mammals and particularly humans by the oral administration of the medicinal composition. The composition comprises water-soluble macromolecular medicaments, a dispersing agent, an auxiliary stabilizing agent, a hydrophobic medium, water and other optional pharmaceutic adjuvants. The preparation method of the composition is simple, and the oral bioavailability of the medicaments can be greatly improved.
Description
Technical field
The present invention relates to be used for the compositions of oral pharmacologically active agent, improve oral administration bioavailability method and by the Orally administered medicine composite for curing of the present invention and/or the method for preventing mammal, especially human diseases.
Background technology
Oral is the best a kind of route of administration of patient's compliance, but along with development of biology, protein and peptide drugs application clinically all is clinical polypeptide drugs commonly used as calcitonin, insulin, thymosin etc. more and more widely, main at present by drug administration by injection, patient's poor compliance.Peroral dosage form is easily accepted by the patient, influences it and sends but the greatest problem of this type of drug oral is physics, the chemistry and biology barrier of body.Various organ, the tissue that must pass before physical barriers such as mucosa and the arrival target spot; The variation of chemical barrier such as pH, bilayer lipid membrane and digestive enzyme etc.; Biological containment such as cytophagy, film transhipment passage etc.Therefore, the bioavailability of most of polypeptide such as calcitonin all is lower than 10% usually.In addition, some be difficult to see through gastrointestinal tract mucous and/or in gastrointestinal tract the oral absorption of unsettled other pharmacologically active agents very poor.For this reason, people overcome focusing on of research on two obstacles at present, promptly how to improve the degraded of the biomembrane permeability and the opposing gastrointestinal enzyme of above-mentioned pharmacologically active agent.
U.S. Patent No. 5773647 and 5866536, WO 00/59863, CN 03818295.5, CN 01820142.3, CN200480017406.5 disclose the pharmaceutical composition of the oral delivery calcitonin that contains modified amino acid, have improved the bioavailability of calcitonin greatly.The complicated process of preparation of preparation, cost height.CN 200610097474.8 discloses the calcitonin oral enteric composition and method of making the same that contains absorption enhancer, has effectively improved the absorption of calcitonin at intestinal.The complicated process of preparation of said preparation, cost height.CN 200910052683.4 discloses calcitonin oral solid lipid nano-particle preparation and preparation method thereof.The complicated process of preparation of said preparation, be difficult to suitability for industrialized production and used organic solvent.
Therefore, need still to develop that a kind of preparation technology is simple, cost is low, have the compositions of the pharmacologically active agent such as the calcitonin of higher oral administration biaavailability.
Summary of the invention
On the one hand, the present invention relates to a kind of compositions that is used for oral pharmacologically active agent, said composition can improve the oral administration biaavailability of pharmacologically active agent, particularly protein and peptide drugs greatly.The clear solution that it comprises pharmacologically active agent and is made of dispersant, auxiliary stabilizer, hydrophobic medium, water and optional other adjuvant.
On the other hand, the present invention relates to a kind of method that improves the oral administration biaavailability of pharmacologically active agent.This method comprises the present composition from effective dose to the individuality of the described pharmacologically active agent of needs that use.
In addition, the present invention relates to a kind of method that treats and/or prevents bone photo related disorders and/or calcium imbalance.This method comprises the present composition to patient's administering therapeutic effective dose, and pharmacologically active agent wherein is a calcitonin.
Compositions of the present invention is stable solution form, and it comprises the pharmacologically active agent as active component.Compositions of the present invention has not only solved the stability problem of pharmacologically active agent in gastrointestinal tract, is enough to satisfy the dosage requirement of clinical use, but also has significantly improved the permeability of the gastrointestinal mucosa of pharmacologically active agent, and product stability is good.This pharmacologically active agent includes but not limited to protein, polypeptide, hormone, polysaccharide, carbohydrate, and their mixture.
The example of pharmacologically active agent includes but not limited to the following activating agent in all sources: interferon, interleukin, insulin, heparin, calcitonin, vancomycin, norvancomycin, desferrioxamine, parathyroid hormone, protease inhibitor, superoxide dismutase, urokinase, Lumbrukinase, streptokinase, asparaginase, urate oxidase, trypsin, hirudin, enkephalin, endorphins, Kallidin I, bacitracin, Gramicidin, thymosin, Thymopentin, brain natriuretic peptide, octreotide, blood vessel function intestinal peptide, thrombin inhibitor, aprotinin, Defibrase, the glucose cerebrosidase, erythropoietin, antigen, monoclonal antibody, growth hormone, somatostatin, corticotropin, gonadotropin releasing hormone, oxytocin, luteinizing hormone releasing hormone, follicle stimulating hormone, melanotropin, oxytocin, gastrin, the fat adrenocortical hormone, the blood vessel 17-hydroxy-11-dehydrocorticosterone, the short urine of anterior chamber sodium is let out hormone, tuftsin, growth hormone, secretin, Pancreozymin, cholecystokinin, angiotensin, thymosin, thymopoietin, thymostimulin, motilin, thrombopoietin, prostaglandin, vassopressin, kallidinogenase, vascellum esoderma inhibin, antimicrobial, insulin like growth factor, nerve growth factor, somatostatin, epidermal growth factor, fibroblast growth factor, platelet derived growth factor, stem cell factor, transforming growth factor, bone morphogenic factor, angiogenesis factor, the vascularization inhibitive factor, thymic humoral factor, serum thymic factor, tumor necrosis factor, colony stimulating factor, thrombin, nucleic acid etc., and the analog of above-claimed cpd, fragment, analogies, derivant, or polyethyleneglycol modified derivant, or their combination.Preferred water dissolubility macromolecular drug.
In the preferred embodiment of the present invention, pharmacologically active agent is albumen, polypeptide, polyose medicament, particularly calcitonin, Low molecular heparin.Calcitonin is usually used in treatment and prevents diseases such as Paget (scleromalacia), hypercalcemia, osteoporosis and rheumatoid arthritis, trophesy, drug-induced neurotrophy disease, acute pancreatitis.Various calcitonins comprise salmon, pig, clcatonin etc.Calcitonin can be any one calcitonin, comprises calcitonin natural, synthetic, reorganization, and the derivant of calcitonin.Said composition can contain the combination in any of single calcitonin or two kinds and two or more calcitonins.The preferred calcitonin of the present invention is synthetic salmon calcitonin.
Compositions of the present invention also comprises the surfactant as dispersant, and this surfactant can make the saline that contains activating agent be evenly dispersed in the hydrophobic medium.Exemplary surfactants comprises:
(1) the natural or hydrogenated vegetable oil of polyoxyethyleneization is as the natural or castor oil hydrogenated of polyoxyethyleneization;
(2) polyoxyethylene sorbitan fatty acid ester is as polyoxyethylene 20 sorbitan monooleate;
(3) polyoxyethylene fatty acid ester is as Myrj 45;
(4) polyoxyethylene aliphatic alcohol ether is as Brij30;
(5) polyoxyethylene-polyoxypropylene copolymer is as Pluronic;
(6) polyox-yethylene-polyoxypropylene block copolymer is as Poloxamer;
(7) sorbitan fatty acid ester is as sorbitan monooleate;
(8) phospholipid, as the lecithin of lecithin, soybean phospholipid, polyoxyethyleneization, and
Their mixture.
In above-mentioned surfactant, advantageous applications polyoxyethylene sorbitan fatty acid ester of the present invention respectively with the mixture of sorbitan fatty acid ester, phospholipid.Be preferably selected from the mixture of mixture, Tween 80 and the phospholipid of Tween 80 and Span 80 especially.
The present composition that comprises calcitonin also comprises auxiliary stabilizer, and it helps each component mixing of compositions is mixed with even, stable, transparent solution.Can be used for auxiliary stabilizer of the present invention and comprise ethanol, propylene glycol, glycerol, low-molecular-weight Polyethylene Glycol, diethylene glycol monoethyl ether, tetrahydrofurfuryl alcohol polyglycol ether, Isosorbide dimethyl ether or their mixture.Preferred diethylene glycol monoethyl ether, propylene glycol, Isosorbide dimethyl ether or their mixture.Be preferably selected from especially: ethanol, propylene glycol, and their mixture.
Compositions of the present invention also comprises the hydrophobic medium compatible with auxiliary stabilizer with described dispersant, can be used for typical hydrophobic medium of the present invention and comprises:
(1) natural vegetable oil or animal oil is as Semen Maydis oil, Oleum Glycines, fish oil;
(2) liquid fatty acid is as oleic acid, linoleic acid;
(3) fatty acid ester is as isopropyl myristate, Ethyl linoleate;
(4) fatty acid glyceride, as glycerol list, two, trioleate, and
Their mixture.Be preferably selected from fatty acid ester, fatty acid glyceride, and their mixture.Be preferably selected from especially: soybean oil, midchain oil, fatty acid glyceride, and their mixture.
Compositions of the present invention comprises that also the promotion activating agent sees through gastrointestinal mucosa and absorbed absorption enhancer, absorption enhancer wherein is selected from bioadhesive high molecular polymer, fatty acid and soap, non-ionic surface active agent, cyclodextrin, chelating agen, azone, and their mixture.Be preferably selected from: chitosan, citric acid, salicylic acid, Capric acid sodium salt, disodium edetate, Tween80, and their mixture.
Can prepare the present composition by the described component of simple mixing.Present composition appearance transparent, good stability.
Can the present composition be prepared into other multiple peroral dosage forms such as oral liquid, hard capsule, soft capsule, micropill, tablet according to conventional method well known in the art.
In addition, compositions of the present invention also comprises pharmaceutically acceptable additive, include but not limited to pH regulator agent, antioxidant, correctives, antiseptic, viscosity-controlling agent, osmotic pressure regulator, plasticizer, lubricant, fluidizer, excipient, diluent etc., or their combination in any.
Compositions of the present invention also can contain transport inhibitors, as p-glycoprotein inhibitors, for example non-ionic surface active agent.
In order to reach purpose of the present invention, the present invention has carried out the pharmacokinetics test and has fallen the blood calcium effect test.
As mentioned above, compositions of the present invention has not only solved the stability problem of calcitonin in gastrointestinal tract, but also has significantly improved the biomembrane permeability of calcitonin, has improved the oral administration biaavailability of calcitonin.
Description of drawings with reference to the accompanying drawings 1 and accompanying drawing 2, by the following description of the present invention, above-mentioned and other purpose of the present invention and feature will be conspicuous.Accompanying drawing 1 has shown the bioavailability behind the embodiment of the invention 2 and the oral and commercially available injection subcutaneous administration of calcitonin solution.Accompanying drawing 2 has shown and has fallen the blood calcium effect behind the embodiment of the invention 2 and the oral and commercially available injection subcutaneous administration of calcitonin solution.
As mentioned above, compositions of the present invention significantly improves the bioavailability of calcitonin oral administration.
Following examples are used to further describe the present invention, but limit the scope of the present invention anything but.
The specific embodiment
Embodiment 1: the preparation of oral liquid
Calcitonin 0.2mg and disodium edetate 1.0mg are dissolved in the 0.5ml normal saline, with component mix homogeneously such as Tween80 1.0mg, Span801.2mg, soybean oil 1.4mg, ethanol 1.1mg, add an amount of sweet and benzalkonium bromide of Bath, mix homogeneously, obtain the clear and bright mixed liquor of 5ml, then with its fill in cillin bottle, add a cover, sealing, radiation sterilization promptly.
Embodiment 2: preparation of soft capsule
Calcitonin 20mg and salicylic acid 10mg are dissolved in the 45ml normal saline, component uniform mixing such as Tween80 91mg, fabaceous lecithin 91mg, midchain oil 182mg, propylene glycol 91mg are dissolved, and add an amount of vitamin E, benzalkonium chloride, be pressed into 1000 soft capsules behind the mix homogeneously.
Embodiment 3: preparation of soft capsule
Low molecular heparin 19mg and sodium deoxycholate 1.6mg are dissolved in the 48ml normal saline, component uniform mixing such as Tween80 76mg, fabaceous lecithin 76mg, suffering/caprin 228mg, propylene glycol 76mg are dissolved, and add an amount of vitamin E, benzalkonium chloride, be pressed into 1000 soft capsules behind the mix homogeneously.
Embodiment 4: the preparation of hard capsule
With calcitonin 20mg, hydroxypropyl cellulose 1.5mg, mannitol 2mg be dissolved in the 45ml normal saline solution 1, with component uniform mixing such as Tween80 60mg, Span20 120mg, midchain oil 90mg, PEG400 180mg dissolve solution 2, with solution 1 and 2 mixings, lyophilization or spray drying get the pastille powder, with conventional preparation method, with mixing granulations such as diluent, disintegrating agent, binding agents, directly be filled into enteric coated capsule and get 1000 hard capsules.
Embodiment 5: the preparation of tablet
With calcitonin 25mg, chitosan 2mg, lactose 2.5mg be dissolved in the 56ml normal saline solution 1, with component uniform mixing such as Tween8056mg, Span20 56mg, Oleum Cocois glyceride 224mg, PEG400 112mg dissolve solution 2, with solution 1 and 2 mixings, lyophilization or spray drying get the pastille powder, with conventional preparation method, with mixing granulations such as diluent, disintegrating agent, binding agents,, or be pressed into outer enteric coated 1000 enteric coatel tablets that promptly get behind the tablet.
Test example 1: pharmacokinetics test
Be to investigate the bioavailability of the salmon calcitonin see calcimar oral administration in the present composition, following preparation of the present invention among the embodiment 2 and calcitonin solution oral administration are carried out pharmacokinetic respectively, relatively the salmon calcitonin see calcimar absorption in vivo.
Get the male and healthy domesticated dog of body weight 10kg ± 1kg, be divided into 2 groups at random, 4 every group.Test fasting in preceding 24 hours, can freely drink water.After weighing according to dosage be respectively 5 μ g/kg (embodiment 2) and 15 μ g/kg (calcitonin solution) with the gavage administration, and give 10ml water subsequently.Regularly get blood in 0.25,0.5,1,1.5,2,3,4,6,8 hour after the administration, measure the content of calcitonin in the blood with radioimmunoassay.Curve such as Fig. 1 during the medicine that records.
The result of Fig. 1 shows that with comparing of calcitonin solution, the bioavailability of embodiments of the invention 2 oral administration administrations is to improve greatly, and therefore preparation of the present invention has improved the oral bioavailability of calcitonin greatly.
Test example 2: fall the blood calcium effect test
Get the male and healthy domesticated dog of body weight 10kg ± 1kg, be divided into 2 groups at random, 4 every group.Test fasting in preceding 24 hours, can freely drink water.After weighing according to dosage be respectively 5 μ g/kg (embodiment 2) and 15 μ g/kg (calcitonin solution) with the gavage administration, give preparation of the present invention and calcitonin solution among the embodiment 2 respectively, and give 10ml water subsequently.Get blood before the administration earlier as blank.Regularly got blood, centrifugal in 0.5,1,1.5,2,3,4,6,8 hour after the administration, get supernatant and adopt OCPC colorimetric method for determining serum calcium ion concentration.What record the results are shown in Figure 2.
The result of Fig. 2 shows, compares with the calcitonin aqueous solution, and the compositions oral administration administration of embodiment 2 has reduced calcium ion level in the serum significantly, has shown the superiority of the present composition.
Invention has been described though utilized above-mentioned specific embodiment, it should be understood that those skilled in the art also can carry out various improvement or change, and they also should be within the scope of the present invention that limits as claims.
Claims (10)
1. one kind is used for liquid preparations for oral administration, and it comprises water-soluble macromolecule medicine, dispersant, auxiliary stabilizer, hydrophobic medium and water and other optional pharmaceutically acceptable auxiliaries.
2. compositions as claimed in claim 1, water-soluble macromolecule medicine wherein is albumen, polypeptide, polyose medicament, is preferably calcitonin, Low molecular heparin.
3. compositions as claimed in claim 2, calcitonin wherein are salmon calcitonin.
4. compositions as claimed in claim 1, dispersant wherein is selected from: the natural or hydrogenated vegetable oil of polyoxyethyleneization, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene fatty acid ester, polyoxyethylene aliphatic alcohol ether, polyoxyethylene-polyoxypropylene copolymer, polyox-yethylene-polyoxypropylene block copolymer, sorbitan fatty acid ester, phospholipid, and their mixture.Be preferably selected from the polyoxyethylene sorbitan fatty acid ester respectively with the mixture of sorbitan fatty acid ester and phospholipid, be preferably selected from the mixture of mixture, Tween 80 and the phospholipid of Tween 80 and Span 80 especially.
5. compositions as claimed in claim 1, auxiliary stabilizer wherein is selected from: ethanol, propylene glycol, glycerol, low-molecular-weight Polyethylene Glycol, diethylene glycol monoethyl ether, tetrahydrofurfuryl alcohol polyglycol ether, Isosorbide dimethyl ether, phospholipid, and their mixture.Be preferably selected from propylene glycol, diethylene glycol monoethyl ether, Isosorbide dimethyl ether, and their mixture, be preferably selected from especially: ethanol, propylene glycol, and their mixture.
6. compositions as claimed in claim 1, hydrophobic medium wherein is selected from: natural vegetable oil or animal oil, liquid fatty acid, fatty acid ester, fatty acid glyceride, and their mixture.Be preferably selected from fatty acid ester, fatty acid glyceride, and their mixture, be preferably selected from especially: soybean oil, midchain oil, fatty acid glyceride, and their mixture.
7. as each described compositions of claim 1-6, wherein contain absorption enhancer.
8. compositions as claimed in claim 7, absorption enhancer wherein selects bioadhesive high molecular polymer, fatty acid and soap, non-ionic surface active agent, cyclodextrin, chelating agen, azone, and their mixture.Be preferably selected from: chitosan, citric acid, salicylic acid, Capric acid sodium salt, disodium edetate, Tween80, and their mixture.
9. be used for improving the purposes of medicine of the oral administration biaavailability of calcitonin in preparation as each described pharmaceutical composition of claim 1-8.
10. be used for the treatment of or prevent purposes in the medicine of bone photo related disorders and/or calcium imbalance etc. in preparation as each described pharmaceutical composition of claim 1-8.
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| CN200910259600.9A CN102100907B (en) | 2009-12-21 | 2009-12-21 | Composition of oral pharmacologic active agent |
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| CN200910259600.9A CN102100907B (en) | 2009-12-21 | 2009-12-21 | Composition of oral pharmacologic active agent |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108969754A (en) * | 2018-09-04 | 2018-12-11 | 深圳大佛药业股份有限公司 | A kind of Salmon Calcitonin Nasal Spray and preparation method thereof |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108969754A (en) * | 2018-09-04 | 2018-12-11 | 深圳大佛药业股份有限公司 | A kind of Salmon Calcitonin Nasal Spray and preparation method thereof |
| CN108969754B (en) * | 2018-09-04 | 2019-06-21 | 深圳大佛药业股份有限公司 | A kind of Salmon Calcitonin Nasal Spray and preparation method thereof |
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