CN103977407A - Oral nanoparticle polypeptide composition tablets and preparation method thereof - Google Patents
Oral nanoparticle polypeptide composition tablets and preparation method thereof Download PDFInfo
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Abstract
The invention relates to a medicinal preparation and a preparation method thereof, and in particular relates to a series of polypeptide thymopentin, thymalfasin and thymosin beta4 combined enzyme inhibitors capable of improving the immunity. An oral preparation is prepared by adopting a nanoparticle technology. A pharmaceutically-acceptable biodegradable high polymer material is coated with a polypeptide medicament for improving the immunity to prepare nanoparticles, and tablets are made by tableting. The medicament-loading nanoparticles prepared by using the preparation method have high bioavailability.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, relate to a kind of confession oral administration nanometer grain peptide composition tablet that improves immunity and preparation method thereof.
Background technology
Along with the development of biological medicine technology, increasing polypeptide protein medicine is researched and developed and is applied to clinical, also brings new challenge to pharmaceutical preparation simultaneously.Unstable and perishable due to polypeptide and protein drug, being made into pharmaceutical preparation stable, safety and efficiently is a complicated large order.At present carry out a large amount of research for the drug-supplying system of polypeptide protein medicine, had for the various new drug-supplying system of different route of administration and see report.
Thymopentin is also a kind of important adjusting immunity polypeptide, and the resistance infection of Thymopentin is relevant with its enhancement TC cytoactive with therapeutical effect.In anti-infectious immunity, appropriate Thymopentin can obviously increase the generation of interferon.Induction and promotion T cell differentiation maturation; Regulate t lymphocyte subset group ratio; Strengthen macrophage phagocytic function, strengthen hematid immunity function, improve the vigor of natural killer cell, improve generation level and the expression of receptor level of interleukin-2.Can be used for malignant tumor patient after chemicotherapy, damnification of immunity function person, the treatment of hepatitis B, great surgical operation and severe infections, autoimmune disease.
Thymalfasin is immunostimulant, is important immune regulator in human body, can be used for treating chronic hepatitis B and strengthens immune system.Also there is the migration of vascular endothelial cells of stimulation simultaneously, promote the effects such as angiogenesis and wound healing, for clinical treatment and the research of hepatitis B, hepatitis C, malignant tumor and immune deficiency disorder etc.Thymalfasin is as a kind of spectrum immunomodulator, and clear mechanism has been that numerous doctors and patients are cognitive also to be accepted.
Extrasin beta 4 is a kind of main actin sequestration molecule in eukaryotic cells, is distributed widely in mammal and other vertebrate Various Tissues and nucleated cell.Although the mechanism of action of its molecular level is still not clear, extrasin beta 4 is closely related with the mankind's much physiology and pathological process.Along with further going deep into of research, extrasin beta 4 potential using value clinically will be developed, and this diagnosis for some diseases, treatment and prevention are all significant.The application of extrasin beta 4 is in recent years mainly at aspects such as wound healing, neoplasm metastasis, revascularizatioies.Protein and peptide drugs biological activity is strong, and relative cost is low, and action target spot is single-minded, has successfully applied in the inapparent field of the chemicals such as heredopathia, chronic disease curative effect.
But due to its poor stability at normal temperatures of polypeptide immune regulator, short, the easily degraded, and human body of biological half-life has certain barrier action to it in vivo, therefore conventional route of administration is taking injection as main.Common formulations is solution type injection agent and lyophilized injectable powder, causes route of administration single, and needs frequent drug administration, brings inconvenience and misery to patient.The Thymic form of administration that improves at present immunity is injecting drug use, and biweekly and above administration, the medication cycle reaches the several months sometimes.
Because oral administration system is easy to use, patient's compliance is high, becomes one of the most popular route of administration.But protein and peptide drugs is due to unstable, if modify without chemistry or preparation, directly oral administration, its bioavailability often only has 0.1%-2% or lower, and clinical use value is little, so become again the route of administration of difficulty maximum.The research emphasis of current oral administration is placed on and improves on its oral administration biaavailability.The reason that affects bioavailability has the self-characteristic of protein and peptide drugs, pH value, digestive enzyme and biomembranous barrier action etc. in body.
The low absorption of gastrointestinal tract to polypeptide drug and enzyme are wherein two biggest obstacles that oral administration faces to the degraded of medicine.Therefore, find suitable absorption site, the first pass effect of avoiding gastrointestinal enzyme degradation and liver is the key of dealing with problems.Except the structure of medicine is carried out to chemical modification, except adding people's enzyme inhibitor, the particulate delivery systems such as liposome, microcapsule, microsphere, nanoparticle also can promote medicine through the circulation of gastrointestinal absorption human blood effectively, improve the oral bioavailability of polypeptide drug.
After proteins and peptides class oral administration of drugs, will reach certain blood drug level, first must overcome the effect of gastrointestinal tract protease, therefore the use of enzyme inhibitor becomes inevitable.Conventional enzyme inhibitor has sodium glycocholate, camostat mesilate, bacitracin, aprotinin, Semen sojae atricolor pancreatin inhibitor etc.
Diameter is at the nanoparticle of 10～100 nm as the little pharmaceutical carrier of a kind of ultra micro, and major advantage is that medicine is carried down and transported to blood system by lymphoid tissue assembly-Peyer ' s under cell bypass or small intestinal.Nanoparticle is because particle diameter is less, and surface area increases, and improves with biomembranous tackness, just can be gathered in a large number Peyer knot after entering intestinal, carries biomacromolecule and sees through biological mucosa with complete form, thereby improve the bioavailability of oral drugs.
Oral administration is a kind of convenience and the mode easily accepted by patient, if can fully solve the absorption of protein and peptide class medicine and the problem of bioavailability, believes that prospect is boundless.
Summary of the invention
The object of the invention is to prepare a kind of immunity nanoparticle peptide composition tablet for oral administration that improves, raising immunity polypeptide drugs are wrapped in pharmaceutically acceptable biodegradated polymer materal, be prepared into nanoparticle, then compression makes tablet, and the drug-carrying nanometer particle bioavailability of utilizing the present invention to prepare is high.
The prepared one of the present invention supplies oral administration nanometer grain peptide composition tablet, comprises and improves immunity polypeptide, enzyme inhibitor, pharmaceutically acceptable biodegradated polymer materal and other pharmaceutic adjuvants.Improve immunity polypeptide and be selected from Thymopentin, thymalfasin, extrasin beta 4 a kind of or its mixture wherein, it accounts for compositions percentage ratio is 0.1%-30%; Enzyme inhibitor is selected from sodium glycocholate, camostat mesilate, bacitracin, aprotinin, Semen sojae atricolor pancreatin inhibitor a kind of or its mixture wherein, and it accounts for compositions percentage ratio is 0.1%-10%; Pharmaceutically acceptable biodegradated polymer materal is selected from polylactic acid (PLA), polyglycolic acid, Poly(D,L-lactide-co-glycolide (PLGA), polylactide, polycaprolactone, polyalkylcyanoacrylate a kind of or its mixture wherein, and it accounts for compositions percentage ratio is 50%-90%; This peptide composition also comprises emulsion stabilizer, excipient, filler, disintegrating agent, binding agent, fluidizer.Emulsion stabilizer is polyvinyl alcohol, and it accounts for compositions percentage ratio is 0.1%-10%; Excipient is selected from sorbitol, mannitol, lactose, sucrose a kind of or its mixture wherein, and it accounts for compositions percentage ratio is 0.1%-5%.Filler is selected from corn starch, dextrin, microcrystalline Cellulose a kind of or its mixture wherein, and it accounts for compositions percentage ratio is 0.1%-5%.Disintegrating agent is selected from crospolyvinylpyrrolidone, crosslinked carboxycellulose sodium a kind of or its mixture wherein, and it accounts for compositions percentage ratio is 0.1%-5%.Binding agent is selected from starch, carboxy-propyl cellulose a kind of or its mixture wherein, and it accounts for compositions percentage ratio is 0.1%-5%.Fluidizer is selected from magnesium stearate, Pulvis Talci a kind of or its mixture wherein, and it accounts for compositions percentage ratio is 0.1%-5%.
The prepared one of the present invention supplies oral administration nanometer grain peptide composition, and its preparation method is as follows:
The first step, first will improve immunity polypeptide, enzyme inhibitor is water-soluble, obtains interior water; Separately biodegradable polymer is dissolved in organic solvent, obtains oil phase; Oil phase and interior water are placed in agitator, and breast is even at a high speed, forms W/O emulsion; Then W/O emulsion is joined in polyvinyl alcohol water solution, breast is even at a high speed, forms W/O/W emulsion;
Second step, by W/O/W emulsion, room temperature lower magnetic force stirs, remove organic solvent, ultracentrifugation obtains nanoparticle precipitation, distilled water wash repeatedly after, centrifugal collection again, add excipient, lyophilization, adds filler, disintegrating agent, binding agent, fluidizer, tabletting makes a kind of for oral administration nanometer grain peptide composition tablet.
Organic solvent of the present invention comprises dichloromethane, chloroform, ethyl acetate, ether, preferably dichloromethane.
Below in conjunction with embodiment, embodiment of the present invention are described in detail, but it will be understood to those of skill in the art that the following example is only for the present invention is described, and should not be considered as limiting scope of the present invention.
Detailed description of the invention:
Embodiment 1
Take 20g Thymopentin, 10g sodium glycocholate is water-soluble, obtains interior water; Take 160g polylactic acid, be dissolved in dichloromethane, obtain oil phase.First interior aqueous phase solution is moved in oil-phase solution, under room temperature, be placed on emulsion dispersion machine at a high speed (30000rpm) breast even 30 seconds, obtain W/O emulsion, then w/o type emulsion is transferred to 50ml concentration and is in 5% poly-vinyl alcohol solution, be placed in the rotating speed with 5000rpm on emulsion dispersion machine, even 1 minute of breast, obtain W/O/W type emulsion, room temperature lower magnetic force stirs, stir 2 hours with 500rpm low speed rotation, remove organic facies, centrifugal, collect gained nanoparticle precipitation, repeatedly wash with distilled water, and then centrifugal collection, add 10g sorbitol, lyophilization, obtain nanoparticle, add again 10g corn starch, 10g crospolyvinylpyrrolidone, 10g starch, 10g magnesium stearate, tabletting obtains a kind of for oral administration nanometer grain peptide composition tablet.
Give respectively the rat injection nanoparticle peptide composition tablet prepared by thymus gland pentapeptide injection and oral the present embodiment that gone on the market, adopt microplate reader algoscopy, record the fluorescence intensity after rat administration, evaluate nanoparticle peptide composition tablet prepared by gone on the market thymus gland pentapeptide injection and the present embodiment pharmacokinetics in rat body.Result shows, after rat single dose intramuscular injection evaluation of thymopentin in solution, 10min reaches peak concentration, and peak concentration is (14.23 ± 2.08) μ g/ mL, then eliminates very soon, and after 12h, blood Chinese medicine concentration, lower than quantitative limit, cannot detect.And give after nanoparticle peptide composition tablet prepared by the present embodiment, 30min reaches peak concentration, but peak concentration significantly reduces, be only (5.74 ± 1.32) μ g/ mL, in 5d, blood drug level is more steady, and 120h still can detect medicine, illustrate that nanoparticle peptide composition tablet prepared by the present embodiment has obvious slow releasing function, action time is longer, and bioavailability is high, and administration is more convenient.
Embodiment 2
Take 30g Thymopentin, 15g camostat mesilate is water-soluble, obtains interior water; Take 200g polyglycolic acid, be dissolved in dichloromethane, obtain oil phase.First interior aqueous phase solution is moved in oil-phase solution, under room temperature, be placed on emulsion dispersion machine at a high speed (30000rpm) breast even 30 seconds, obtain W/O emulsion, then w/o type emulsion is transferred to 50ml concentration and is in 5% poly-vinyl alcohol solution, be placed in the rotating speed with 5000rpm on emulsion dispersion machine, even 1 minute of breast, obtain W/O/W type emulsion, room temperature lower magnetic force stirs, with the rotating speed stirring at low speed of 500rpm 2 hours, remove organic solvent, centrifugal, collect gained nanoparticle precipitation, repeatedly wash with distilled water, and then centrifugal collection, add 15g mannitol, lyophilization, lyophilization, obtain nanoparticle, add again 15g dextrin, 15g is cross-linked carboxycellulose sodium, 15g carboxy-propyl cellulose, 15g Pulvis Talci, tabletting obtains a kind of for oral administration nanometer grain peptide composition tablet.
Give respectively the rat injection nanoparticle peptide composition tablet prepared by thymus gland pentapeptide injection and oral the present embodiment that gone on the market, adopt microplate reader algoscopy, record the fluorescence intensity after rat administration, evaluate nanoparticle peptide composition tablet prepared by gone on the market thymus gland pentapeptide injection and the present embodiment pharmacokinetics in rat body.Result shows, after rat single dose intramuscular injection evaluation of thymopentin in solution, 10min reaches peak concentration, and peak concentration is (14.23 ± 2.08) μ g/ mL, then eliminates very soon, and after 12 h, blood Chinese medicine concentration, lower than quantitative limit, cannot detect.And give after nanoparticle peptide composition tablet prepared by the present embodiment, 25min reaches peak concentration, but peak concentration significantly reduces, be only (7.92 ± 1.64) μ g/ mL, in 3d, blood drug level is more steady, and 100h still can detect medicine, illustrate that nanoparticle peptide composition tablet prepared by the present embodiment has obvious slow releasing function, action time is longer, and bioavailability is high, and administration is more convenient.
Embodiment 3
Take 40g Thymopentin, 15g bacitracin is water-soluble, obtains interior water; Take 180g Poly(D,L-lactide-co-glycolide, be dissolved in dichloromethane, obtain oil phase.First interior aqueous phase solution is moved in oil-phase solution, under room temperature, be placed on emulsion dispersion machine at a high speed (30000rpm) breast even 30 seconds, obtain W/O emulsion, then w/o type emulsion is transferred to 50ml concentration and is in 5% poly-vinyl alcohol solution, be placed in the rotating speed with 5000rpm on emulsion dispersion machine, even 1 minute of breast, obtain W/O/W type emulsion, room temperature magnetic agitation, with the rotating speed stirring at low speed of 500rpm 2 hours, centrifugal, collect gained nanoparticle precipitation, repeatedly wash with distilled water, and then centrifugal collection, add 10g sucrose, lyophilization, obtain nanoparticle, add again 10g microcrystalline Cellulose, 10g crospolyvinylpyrrolidone, 10g starch, 10g Pulvis Talci, tabletting obtains a kind of for oral administration nanometer grain peptide composition tablet.
Give respectively the rat injection nanoparticle peptide composition tablet prepared by thymus gland pentapeptide injection and oral the present embodiment that gone on the market, adopt microplate reader algoscopy, record the fluorescence intensity after rat administration, evaluate nanoparticle peptide composition tablet prepared by gone on the market thymus gland pentapeptide injection and the present embodiment pharmacokinetics in rat body.Result shows, after rat single dose intramuscular injection evaluation of thymopentin in solution, 10min reaches peak concentration, and peak concentration is (14.23 ± 2.08) μ g/ mL, then eliminates very soon, and after 12 h, blood Chinese medicine concentration, lower than quantitative limit, cannot detect.And give after nanoparticle peptide composition tablet prepared by the present embodiment, 20min reaches peak concentration, but peak concentration significantly reduces, be only (5.19 ± 1.35) μ g/ mL, in 4d, blood drug level is more steady, and 150h still can detect medicine, illustrate that nanoparticle peptide composition tablet prepared by the present embodiment has obvious slow releasing function, action time is longer, and bioavailability is high, and administration is more convenient.
Embodiment 4
Take 40g thymalfasin, 10g aprotinin is water-soluble, obtains interior water; Take 150g polylactide, be dissolved in dichloromethane, obtain oil phase; Compound concentration is 5% poly-vinyl alcohol solution 50ml.First interior aqueous phase solution is moved in oil-phase solution, under room temperature, be placed on emulsion dispersion machine at a high speed (30000rpm) breast even 30 seconds, obtain W/O emulsion, then w/o type emulsion is transferred to 20ml concentration and is in 5% poly-vinyl alcohol solution, be placed in the rotating speed with 5000rpm on emulsion dispersion machine, even 1 minute of breast, obtain W/O/W type emulsion, room temperature magnetic agitation, with the rotating speed stirring at low speed of 500rpm 2 hours, remove organic solvent, centrifugal, collect gained nanoparticle precipitation, repeatedly wash with distilled water, and then centrifugal collection, add 10g lactose, lyophilization, obtain nanoparticle, add again 10g corn starch, 10g crospolyvinylpyrrolidone, 10g carboxymethyl cellulose, 10g Pulvis Talci, tabletting obtains a kind of for oral administration nanometer grain peptide composition tablet.
Give respectively the rat nanoparticle peptide composition tablet prepared by injection thymalfasin and oral the present embodiment that gone on the market, adopt microplate reader algoscopy, record the fluorescence intensity after rat administration, evaluate nanoparticle peptide composition tablet prepared by gone on the market injection thymalfasin and the present embodiment pharmacokinetics in rat body.Result shows, after rat single dose intramuscular injection evaluation of thymopentin in solution, 15min reaches peak concentration, and peak concentration is (19.38 ± 2.47) μ g/ mL, then eliminates very soon, and after 10 h, blood Chinese medicine concentration, lower than quantitative limit, cannot detect.And give after nanoparticle peptide composition tablet prepared by the present embodiment, 30min reaches peak concentration, but peak concentration significantly reduces, be only (9.49 ± 2.07) μ g/ mL, in 4d, blood drug level is more steady, and 130h still can detect medicine, illustrate that nanoparticle peptide composition tablet prepared by the present embodiment has obvious slow releasing function, action time is longer, and bioavailability is high, and administration is more convenient.
Embodiment 5
Take 40g thymalfasin, 20g Semen sojae atricolor pancreatin inhibitor is water-soluble, obtains interior water; Take 320g polycaprolactone, be dissolved in dichloromethane, obtain oil phase; Compound concentration is 5% poly-vinyl alcohol solution 50ml.First interior aqueous phase solution is moved in oil-phase solution, under room temperature, be placed on emulsion dispersion machine at a high speed (30000rpm) breast even 30 seconds, obtain W/O emulsion, then w/o type emulsion is transferred to 20ml concentration and is in 5% poly-vinyl alcohol solution, be placed in the rotating speed with 5000rpm on emulsion dispersion machine, even 1 minute of breast, obtain W/O/W type emulsion, room temperature magnetic agitation, with the rotating speed stirring at low speed of 500rpm 2 hours, centrifugal, collect gained nanoparticle precipitation, repeatedly wash with distilled water, and then centrifugal collection, add 10g lactose, 10g sorbitol, lyophilization, obtain nanoparticle, add again 15g dextrin, 5g microcrystalline Cellulose, 10g crospolyvinylpyrrolidone, 5g is cross-linked carboxycellulose sodium, 15g starch, 15g magnesium stearate, tabletting obtains a kind of for oral administration nanometer grain peptide composition tablet.
Give respectively the rat nanoparticle peptide composition prepared by injection thymalfasin and oral the present embodiment that gone on the market, adopt microplate reader algoscopy, record the fluorescence intensity after rat administration, evaluate nanoparticle peptide composition prepared by gone on the market injection thymalfasin and the present embodiment pharmacokinetics in rat body.Result shows, after rat single dose intramuscular injection evaluation of thymopentin in solution, 15min reaches peak concentration, and peak concentration is (19.38 ± 2.47) μ g/ mL, then eliminates very soon, and after 10 h, blood Chinese medicine concentration, lower than quantitative limit, cannot detect.And give after nanoparticle peptide composition prepared by the present embodiment, 50min reaches peak concentration, but peak concentration significantly reduces, be only (7.23 ± 2.12) μ g/ mL, in 6d, blood drug level is more steady, and 180h still can detect medicine, illustrate that nanoparticle peptide composition prepared by the present embodiment has obvious slow releasing function, action time is longer, and bioavailability is high, and administration is more convenient.
Embodiment 6
Take 40g thymalfasin, 5g sodium glycocholate, 5g camostat mesilate are water-soluble, obtain interior water; Take 40g polycaprolactone, 40g polyglycolic acid, be dissolved in dichloromethane, obtain oil phase; Compound concentration is 5% poly-vinyl alcohol solution 50ml.First interior aqueous phase solution is moved in oil-phase solution, under room temperature, be placed on emulsion dispersion machine at a high speed (30000rpm) breast even 30 seconds, obtain W/O emulsion, then w/o type emulsion is transferred to 20ml concentration and is in 5% poly-vinyl alcohol solution, be placed in the rotating speed with 5000rpm on emulsion dispersion machine, even 1 minute of breast, obtain W/O/W type emulsion, move in the poly-vinyl alcohol solution of 500ml0.5%, magnetic agitation, with the rotating speed stirring at low speed of 500rpm 2 hours, centrifugal, collect gained nanoparticle precipitation, repeatedly wash with distilled water, and then centrifugal collection, add 8g mannitol, lyophilization, obtain nanoparticle, add again 8g corn starch, 8g crospolyvinylpyrrolidone, 4g starch, 4g carboxy-propyl cellulose, 8g magnesium stearate, tabletting obtains a kind of for oral administration nanometer grain peptide composition tablet.
Give respectively the rat nanoparticle peptide composition tablet prepared by injection thymalfasin and oral the present embodiment that gone on the market, adopt microplate reader algoscopy, record the fluorescence intensity after rat administration, evaluate nanoparticle peptide composition prepared by gone on the market injection thymalfasin and the present embodiment pharmacokinetics in rat body.Result shows, after rat single dose intramuscular injection evaluation of thymopentin in solution, 15min reaches peak concentration, and peak concentration is (19.38 ± 2.47) μ g/ mL, then eliminates very soon, and after 10 h, blood Chinese medicine concentration, lower than quantitative limit, cannot detect.And give after nanoparticle peptide composition tablet prepared by the present embodiment, 50min reaches peak concentration, but peak concentration significantly reduces, be only (8.49 ± 1.16) μ g/ mL, in 5d, blood drug level is more steady, and 160h still can detect medicine, illustrate that nanoparticle peptide composition tablet prepared by the present embodiment has obvious slow releasing function, action time is longer, and bioavailability is high, and administration is more convenient.
Embodiment 7
Take 30g extrasin beta 4,5g bacitracin, 5g aprotinin are water-soluble, obtain interior water; Take 50g polylactide, 50g polycaprolactone, be dissolved in dichloromethane, obtain oil phase; Compound concentration is 5% poly-vinyl alcohol solution 50ml.First interior aqueous phase solution is moved in oil-phase solution, under room temperature, be placed on emulsion dispersion machine at a high speed (30000rpm) breast even 30 seconds, obtain W/O emulsion, then w/o type emulsion is transferred to 20ml concentration and is in 5% poly-vinyl alcohol solution, be placed in the rotating speed with 5000rpm on emulsion dispersion machine, even 1 minute of breast, obtain W/O/W type emulsion, room temperature lower magnetic force stirs, with the rotating speed stirring at low speed of 500rpm 2 hours, remove organic solvent, centrifugal, collect gained nanoparticle precipitation, repeatedly wash with distilled water, and then centrifugal collection, add 8g mannitol, lyophilization, obtain nanoparticle, add again 8g microcrystalline Cellulose, 8g crospolyvinylpyrrolidone, 8g starch, 8g magnesium stearate, tabletting obtains a kind of for oral administration nanometer grain peptide composition tablet.
Give respectively the rat nanoparticle peptide composition prepared by injection thymalfasin and oral the present embodiment that gone on the market, adopt microplate reader algoscopy, record the fluorescence intensity after rat administration, evaluate nanoparticle peptide composition prepared by gone on the market injection thymalfasin and the present embodiment pharmacokinetics in rat body.Result shows, after rat single dose intramuscular injection evaluation of thymopentin in solution, 19min reaches peak concentration, and peak concentration is (15.29 ± 2.37) μ g/ mL, then eliminates very soon, and after 12 h, blood Chinese medicine concentration, lower than quantitative limit, cannot detect.And give after nanoparticle peptide composition prepared by the present embodiment, 30min reaches peak concentration, but peak concentration significantly reduces, be only (6.37 ± 2.18) μ g/ mL, in 3d, blood drug level is more steady, and 100h still can detect medicine, illustrate that nanoparticle peptide composition prepared by the present embodiment has obvious slow releasing function, action time is longer, and bioavailability is high, and administration is more convenient.
Embodiment 8
Take 30g extrasin beta 4,15g sodium glycocholate is water-soluble, obtains interior water; Take 150g Poly(D,L-lactide-co-glycolide, be dissolved in dichloromethane, obtain oil phase; Compound concentration is 5% poly-vinyl alcohol solution 50ml.First interior aqueous phase solution is moved in oil-phase solution, under room temperature, be placed on emulsion dispersion machine at a high speed (30000rpm) breast even 30 seconds, obtain W/O emulsion, then w/o type emulsion is transferred to 20ml concentration and is in 5% poly-vinyl alcohol solution, be placed in the rotating speed with 5000rpm on emulsion dispersion machine, even 1 minute of breast, obtain W/O/W type emulsion, room temperature lower magnetic force stirs, with the rotating speed stirring at low speed of 500rpm 2 hours, remove organic solvent, centrifugal, collect gained nanoparticle precipitation, repeatedly wash with distilled water, and then centrifugal collection, add 10g lactose, lyophilization, obtain nanoparticle, add again 10g dextrin, 10g is cross-linked carboxycellulose sodium, 10g carboxy-propyl cellulose, 10g Pulvis Talci, tabletting obtains a kind of for oral administration nanometer grain peptide composition tablet.
Give respectively the rat nanoparticle peptide composition tablet prepared by injection thymalfasin and oral the present embodiment that gone on the market, adopt microplate reader algoscopy, record the fluorescence intensity after rat administration, evaluate nanoparticle peptide composition tablet prepared by gone on the market injection thymalfasin and the present embodiment pharmacokinetics in rat body.Result shows, after rat single dose intramuscular injection evaluation of thymopentin in solution, 19min reaches peak concentration, and peak concentration is (15.29 ± 2.37) μ g/ mL, then eliminates very soon, and after 12 h, blood Chinese medicine concentration, lower than quantitative limit, cannot detect.And give after nanoparticle peptide composition tablet prepared by the present embodiment, 30min reaches peak concentration, but peak concentration significantly reduces, be only (12.12 ± 1.45) μ g/ mL, in 2d, blood drug level is more steady, and 80h still can detect medicine, illustrate that nanoparticle peptide composition tablet prepared by the present embodiment has obvious slow releasing function, action time is longer, and bioavailability is high, and administration is more convenient.
Embodiment 9
Take 30g extrasin beta 4,10g bacitracin is water-soluble, obtains interior water; Take 250g polylactic acid, be dissolved in dichloromethane, obtain oil phase; Compound concentration is 5% poly-vinyl alcohol solution 50ml.First interior aqueous phase solution is moved in oil-phase solution, under room temperature, be placed on emulsion dispersion machine at a high speed (30000rpm) breast even 30 seconds, obtain W/O emulsion, then w/o type emulsion is transferred to 20ml concentration and is in 5% poly-vinyl alcohol solution, be placed in the rotating speed with 5000rpm on emulsion dispersion machine, even 1 minute of breast, obtain W/O/W type emulsion, room temperature lower magnetic force stirs, with the rotating speed stirring at low speed of 500rpm 2 hours, remove organic solvent, centrifugal, collect gained nanoparticle precipitation, repeatedly wash with distilled water, and then centrifugal collection, add 10g lactose, lyophilization, obtain nanoparticle, add again 10g microcrystalline Cellulose, 10g crospolyvinylpyrrolidone, 10g starch, 10g Pulvis Talci, tabletting obtains a kind of for oral administration nanometer grain peptide composition tablet.
Give respectively the rat nanoparticle peptide composition tablet prepared by injection thymalfasin and oral the present embodiment that gone on the market, adopt microplate reader algoscopy, record the fluorescence intensity after rat administration, evaluate nanoparticle peptide composition tablet prepared by gone on the market injection thymalfasin and the present embodiment pharmacokinetics in rat body.Result shows, after rat single dose intramuscular injection evaluation of thymopentin in solution, 19min reaches peak concentration, and peak concentration is (15.29 ± 2.37) μ g/ mL, then eliminates very soon, and after 12 h, blood Chinese medicine concentration, lower than quantitative limit, cannot detect.And give after nanoparticle peptide composition tablet prepared by the present embodiment, 90min reaches peak concentration, but peak concentration significantly reduces, be only (4.78 ± 1.08) μ g/ mL, in 12d, blood drug level is more steady, and 300h still can detect medicine, illustrate that nanoparticle peptide composition tablet prepared by the present embodiment has obvious slow releasing function, action time is longer, and bioavailability is high, and administration is more convenient.
Claims (9)
1. one kind supplies oral administration nanometer grain peptide composition tablet, it is characterized in that, the described oral administration nanometer grain peptide composition that supplies comprises raising immunity polypeptide, enzyme inhibitor, pharmaceutically acceptable biodegradated polymer materal and emulsion stabilizer, excipient, filler, disintegrating agent, binding agent, fluidizer.
2. according to claim 1 a kind of for oral administration nanometer grain peptide composition tablet, it is characterized in that, described raising immunity polypeptide is selected from Thymopentin, thymalfasin, extrasin beta 4 a kind of or its mixture wherein, and it accounts for nano-particle composition 0.1%-30%.
3. a kind of oral administration nanometer grain peptide composition tablet that supplies according to claim 1, is characterized in that, described enzyme inhibitor is selected from sodium glycocholate, camostat mesilate, bacitracin, aprotinin, Semen sojae atricolor pancreatin inhibitor a kind of or its mixture wherein.
4. according to claim 1 a kind of for oral administration nanometer grain peptide composition tablet, it is characterized in that, described pharmaceutically acceptable biodegradated polymer materal is selected from polylactic acid (PLA), polyglycolic acid, Poly(D,L-lactide-co-glycolide (PLGA), polylactide, polycaprolactone, polyalkylcyanoacrylate a kind of or its mixture wherein.
5. a kind of oral administration nanometer grain peptide composition tablet that supplies according to claim 1, is characterized in that, described one also comprises emulsion stabilizer, excipient, filler, disintegrating agent, binding agent, fluidizer for oral administration nanometer grain peptide composition.
6. according to claim 5 a kind of for oral administration nanometer grain peptide composition tablet, it is characterized in that, described emulsion stabilizer is polyvinyl alcohol, described excipient is selected from sorbitol, mannitol, lactose, sucrose a kind of or its mixture wherein, described filler is selected from corn starch, dextrin, microcrystalline Cellulose a kind of or its mixture wherein, disintegrating agent is selected from crospolyvinylpyrrolidone, crosslinked carboxycellulose sodium a kind of or its mixture wherein, binding agent is selected from starch, carboxy-propyl cellulose a kind of or its mixture wherein, fluidizer is selected from magnesium stearate, Pulvis Talci a kind of or its mixture wherein.
7. according to claim 5 a kind of for oral administration nanometer grain peptide composition tablet, it is characterized in that, by mass percentage, described raising immunity polypeptide accounts for 0.1%-30%, and described pharmaceutically acceptable macromolecular material accounts for 50%-90%, and affiliated enzyme inhibitor accounts for 0.1%-10%, described emulsion stabilizer accounts for 0.1%-10%, excipient accounts for 0.1%-5%, filler accounts for 0.1%-5%, disintegrating agent accounts for 0.1%-5%, and binding agent accounts for 0.1%-5%, and fluidizer accounts for 0.1%-5%.
8. a kind of oral administration nanometer grain peptide composition tablet that supplies according to claim 1, is characterized in that, its preparation method is as follows:
The first step, first will improve immunity polypeptide, enzyme inhibitor is water-soluble, obtains interior water; Separately biodegradable polymer is dissolved in organic solvent, obtains oil phase; Oil phase and interior water are placed in agitator, and breast is even at a high speed, forms W/O emulsion; Then W/O emulsion is joined in distilled water, breast is even at a high speed, forms W/O/W emulsion;
Second step, W/O/W emulsion, room temperature lower magnetic force stirs, remove organic facies, ultracentrifugation obtains nanoparticle precipitation, distilled water wash repeatedly after, centrifugal collection, adds excipient again, lyophilization, obtain nano-particle composition, add again filler, disintegrating agent, binding agent, fluidizer, tabletting makes a kind of for oral administration nanometer grain peptide composition tablet.
9. a kind of for oral administration nanometer grain peptide composition method for preparing tablet thereof according to claim 8, it is characterized in that: described organic solvent comprises dichloromethane, chloroform, ethyl acetate, ether, preferably dichloromethane.
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN111297820A (en) * | 2020-03-25 | 2020-06-19 | 哈高科白天鹅药业集团有限公司 | Thymosin enteric-coated tablet and preparation method thereof |
| CN111494600A (en) * | 2019-06-24 | 2020-08-07 | 南京安吉生物科技有限公司 | Medicine composition and medicine for treating hypoimmunity diseases |
| CN111714469A (en) * | 2019-03-22 | 2020-09-29 | 苏州特瑞药业有限公司 | Thymalfasin preparation and preparation method thereof |
| CN112138147A (en) * | 2019-06-10 | 2020-12-29 | 苏州兰鼎生物制药有限公司 | Oral medicine composition of thymalfasin or thymopentin |
| CN113058039A (en) * | 2019-12-14 | 2021-07-02 | 苏州兰鼎生物制药有限公司 | Oral medicine composition of thymalfasin or thymopentin |
| CN113230386A (en) * | 2021-03-07 | 2021-08-10 | 合肥天汇孵化科技有限公司 | Thymalfasin composition and application thereof |
| CN117643620A (en) * | 2023-11-07 | 2024-03-05 | 湖北健肽生物科技有限公司 | Fish collagen peptide, composite nanoparticle, emulsion and application thereof in antihypertensive and/or antithrombotic |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111714469A (en) * | 2019-03-22 | 2020-09-29 | 苏州特瑞药业有限公司 | Thymalfasin preparation and preparation method thereof |
| CN111714469B (en) * | 2019-03-22 | 2023-10-03 | 苏州特瑞药业股份有限公司 | Thymalfasin preparation and preparation method thereof |
| CN112138147A (en) * | 2019-06-10 | 2020-12-29 | 苏州兰鼎生物制药有限公司 | Oral medicine composition of thymalfasin or thymopentin |
| CN112138147B (en) * | 2019-06-10 | 2024-04-09 | 苏州兰鼎生物制药有限公司 | Oral pharmaceutical composition of thymalfasin or thymalpentapeptide |
| CN111494600A (en) * | 2019-06-24 | 2020-08-07 | 南京安吉生物科技有限公司 | Medicine composition and medicine for treating hypoimmunity diseases |
| CN113058039A (en) * | 2019-12-14 | 2021-07-02 | 苏州兰鼎生物制药有限公司 | Oral medicine composition of thymalfasin or thymopentin |
| CN111297820A (en) * | 2020-03-25 | 2020-06-19 | 哈高科白天鹅药业集团有限公司 | Thymosin enteric-coated tablet and preparation method thereof |
| CN113230386A (en) * | 2021-03-07 | 2021-08-10 | 合肥天汇孵化科技有限公司 | Thymalfasin composition and application thereof |
| CN113230386B (en) * | 2021-03-07 | 2022-04-12 | 合肥天汇孵化科技有限公司 | Thymalfasin composition and application thereof |
| CN117643620A (en) * | 2023-11-07 | 2024-03-05 | 湖北健肽生物科技有限公司 | Fish collagen peptide, composite nanoparticle, emulsion and application thereof in antihypertensive and/or antithrombotic |
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| CN103977407B (en) | 2016-09-14 |
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