CN101108246A - Thymus gland pentapeptide oral intestine-dissolved formulated product and method of preparing the same and use thereof - Google Patents
Thymus gland pentapeptide oral intestine-dissolved formulated product and method of preparing the same and use thereof Download PDFInfo
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Abstract
The invention provides a Thymopentin Oral Enteric-coated Agent, which takes thymopentin of effective dosage as the active ingredient and enteric-coated agent as its accessories. Each dosage contains 5mg to 150 mg thymopentin. The invention also provides the preparation method and usage of the enteric-coated agent. The medicine effect tests prove that the medicine has the same indication and efficacy as the injections and can overcome that the gastrointestinal enzyme will easily degrade the thumopentin into amino acid and small peptide so as to lose the activity when orally taking the Thymopentin; the thumopentin can not easily penetrate the gastrointestinal mucosa, resulting in low bioavailability; and the liver has the First-pass effect on the thymopentin. The invention opens a new way to apply thumopentin and increases the patients' compliance.
Description
Technical field
The present invention relates to a kind of oral enteric preparation of peptide medicament, particularly, is to be the oral enteric preparation that active component is prepared from the Thymopentin, belongs to drug world.
Background technology
Present nearly 40 peptide species class medicines on the domestic and international market enjoy the patient to favor owing to polypeptide drug has high activity, low dosage, hypotoxic characteristics.But owing to peptide medicament is easily become aminoacid, little peptide to lose activity by the enzymatic degradation in gastric acid, the gastrointestinal when oral, also being difficult for seeing through gastrointestinal mucosa is absorbed by the body, simultaneously, gastrointestinal tract, liver have characteristics such as first pass effect influence to oral peptide medicament, and having limited the oral administration of peptide medicament, the route of administration of existing peptide medicament number extremely greatly is injection type, uses rather inconvenience, the intravital half-life is short low with bioavailability, and has seriously limited its market potential.
Thymopentin (Thymopoietin, TP5) be the pentapeptide of synthetic, its amino acid sequence and structure and thymopoietin II (Thymopoietin II, the pentapeptide fragment at immunocompetence center TP II), promptly 32-36 amino acids sequence (essence-Lai-Radix Asparagi-figured silk fabrics-tyrosine) is formed identical, it is thymopoietin II important function active part, Thymopentin has the whole physiological functions identical with thymopoietin II, promptly has two-ways regulation functions of immune system (Goldstein G, et al.Surv Immunol Res, 185:2 (SI): 1).Thymopentin can promote the differentiation and the growth of thymus and periphery T cell, and body's immunological function is had dual regulation, can make too high or too low immunoreation trend normal.Thymopentin is mainly used in treatment tumor, immunologic hypofunction and autoimmune disease at present, and can regulate the thymus function that goes down, and makes the unbalance immunologic function normalization of body, promotes the growth and the differentiation of thymocyte cell.Atrophy of thymus gland and the hypofunction that causes because of age and other factors had important regulatory role.Thymopentin is a kind of medicine as safe as a house, no matter subcutaneous injection or intravenously administrable, all little toxic and side effects.Therefore Thymopentin is a kind of immunomodulator of new type of safe, and its immune system class drug use person that is developed as has increased a kind of selection safely and effectively.
The same with most peptide medicaments, the Thymopentin preparation that has gone on the market at present is an injection both at home and abroad, and using method is: each 1mg, and once a day, 15-30mg is a course of treatment, intramuscular injection; Before the operation, and after the operation, once a day; Before and after radiotherapy, the chemotherapy, once a day.Because the patient is significantly smaller than oral formulations to the compliance of ejection preparation, the route of administration of medicine changes, at concrete indication and drug effect all can not determine, and, the relevant report of the new route of administration of Thymopentin is not arranged at present at different molecular weight, its supplementary product kind of different types of peptide, consumption difference.
Summary of the invention
In order to overcome above-mentioned deficiency, technical problem to be solved by this invention has provided a kind of thymus gland pentapeptide oral intestine-dissolved formulated product, and it is to be the oral enteric preparation that active component is prepared from the Thymopentin.The present invention also provides the preparation method and the purposes of this oral enteric preparation.
The invention provides a kind of oral Thymopentin enteric coated preparation, it is that Thymopentin by effective dose is an active component, add the enteric coated preparation that pharmaceutically acceptable enteric coated preparation is prepared from adjuvant, wherein, Thymopentin 5～150mg is contained in every preparation unit, take every day 1 time, take 1 preparation unit at every turn.
Described preparation unit is meant the dosage forms unit of pharmacy conventional formulation such as every of tablet, every capsules of capsule, granule every bag.
Further, every preparation unit contains Thymopentin 15～50mg.
Wherein, the oral Thymopentin enteric coated preparation of the present invention is to be prepared from by the adjuvant that contains the following weight proportioning: 5～100 parts of absorption enhancers, 7～70 parts of enzyme inhibitors, 5～15 parts of coating materials.
Wherein, described absorption enhancer is one or more in tristerin, polyacrylic acid crosslinked polymer, fatty acid, cholic acid, deoxycholic acid and its esters; Described enzyme inhibitor is for pressing down in enzyme peptide aprotinin, aprotinin, pepsin inhibitor, sodium glycocholate, camostat mesilate camostat mesilate, bacitracin bacitracin, the Semen sojae atricolor pancreatin inhibitor etc. one or more.
Wherein, described coating materials is the adjuvant that contains the following weight proportioning: 1～5 part of antiplastering aid, 0.4～3 part of plasticizer, 3.6～7 parts of enteric solubility adjuvants.Described antiplastering aid is one or more in Pulvis Talci, magnesium stearate, the micropowder silica gel; Plasticizer is one or more in propylene glycol, glycerol, Polyethylene Glycol, glycerol triethyl, triethyl citrate, acetyl monoglyceride, phthalate, the Oleum Ricini; The enteric solubility adjuvant is one or more in crylic acid resin, hydroxypropyl cellulose class, arabic gum, the Lac.
Further, described enteric coated preparation also comprises the adjuvant of following weight proportioning:
7～700 parts of filleies, 0～100 part of disintegrating agent, 0～10 part of lubricant, 0～10 part of fluidizer.
Wherein, described filler is one or more in microcrystalline Cellulose, mannitol, lactose, the amylum pregelatinisatum; Described disintegrating agent is one or more in crospolyvinylpyrrolidone, low-substituted hydroxypropyl cellulose, carboxymethyl starch sodium, microcrystalline Cellulose, the sodium alginate; Described lubricant, fluidizer are one or more in Pulvis Talci, micropowder silica gel, hydrogenated vegetable oil, Polyethylene Glycol, stearic acid, magnesium stearate, the dicalcium phosphate dihydrate.
Described preparation is tablet, capsule, pilule, pellet, granule, dry suspension, suspensoid.
Described tablet is enteric coatel tablets, and it is that the Thymopentin and the adjuvant that contain the following weight proportioning are prepared from:
15～50 parts of Thymopentin, 5～30 parts of NaTDCs, 15～30 parts of tristerins, 10～20 parts in polyacrylic acid crosslinked polymer, 7～70 parts of aprotiniies, 10～700 parts of amylum pregelatinisatums, 20～100 parts of crospolyvinylpyrrolidone, 2～10 parts of micropowder silica gels, 2～10 parts of magnesium stearate, 5～15 parts of coating materials.
Further, it is that Thymopentin and the adjuvant that contains the following weight proportioning is prepared from:
5 parts of Thymopentin, 10 parts of NaTDCs, 30 parts of tristerins, 10～20 parts in polyacrylic acid crosslinked polymer, 7 parts of aprotiniies, 700 parts of amylum pregelatinisatums, 20 parts of crospolyvinylpyrrolidone, 10 parts of micropowder silica gels, 10 parts of magnesium stearate, 5～15 parts of coating materials.
Further, it is prepared from by the Thymopentin and the adjuvant of following weight proportioning:
5 parts of Thymopentin, 10 parts of NaTDCs, 30 parts of tristerins, 10～20 parts in polyacrylic acid crosslinked polymer, 7 parts of aprotiniies, 700 parts of amylum pregelatinisatums, 20 parts of crospolyvinylpyrrolidone, 10 parts of micropowder silica gels, 10 parts of magnesium stearate, 5～15 parts of coating materials.
Wherein, weightening finish is behind the coating of described tablet: 5～15mg/cm
2, enteric coated tablet hardness be 3～7kgN.
Can carry out being reprocessed into corresponding dosage forms behind the full powder coating to material, wherein the coating weightening finish be 5～15mg/cm
2Perhaps material is prepared into granule, to being reprocessed into corresponding dosage forms after the granule coating, wherein the coating weightening finish is 5～15mg/cm
2Another kind method is that Thymopentin is become liposome with absorption enhancer, enzyme inhibitor and enteric material co-production, gets liposome micropill (ball) or granule after drying, becomes corresponding dosage forms by further processing and preparing again.
The present invention also provides a kind of preparation method for preparing this oral Thymopentin enteric coated preparation, it is to be active component with the Thymopentin, adds absorption enhancer, enzyme inhibitor, is pressed into plain sheet, by the enteric coated enteric coatel tablets that are prepared into of coating materials, comprise following concrete steps again:
A, the Thymopentin that takes by weighing following weight proportion and adjuvant:
5～50 parts of Thymopentin, 5～100 parts of absorption enhancers, 7～70 parts of enzyme inhibitors, 10～700 parts of filleies, 0～100 part of disintegrating agent, 0～10 part of lubricant, 0～10 part of fluidizer are crossed the pharmacopeia sieve respectively No. 3, and be standby;
B, Thymopentin and each the adjuvant equivalent mix homogeneously that progressively increases is surveyed intermediate content, and it is heavy to calculate sheet, dry powder direct tabletting, during tabletting the hardness of control strip at 3～7kgN, standby;
C, preparation coating materials carry out coating to the tablet that has suppressed, and the coating weightening finish is: 5～15mg/cm
2, packing promptly.
The present invention also provides the purposes of this oral Thymopentin enteric coated preparation in the immunoregulatory medicine of preparation.
The present invention also provides a kind of preparation method for preparing this oral Thymopentin enteric coated preparation, it is to be active component with the Thymopentin, adds absorption enhancer, enzyme inhibitor, is pressed into plain sheet, by the enteric coated enteric coatel tablets that are prepared into of coating materials, comprise following concrete steps again:
A, the Thymopentin that takes by weighing following weight proportion and adjuvant:
5～50 parts of Thymopentin, 5～100 parts of absorption enhancers, 7～70 parts of enzyme inhibitors, 10～700 parts of filleies, 0～100 part of disintegrating agent, 0～10 part of lubricant, 0～10 part of fluidizer are crossed the pharmacopeia sieve respectively No. 3, and be standby;
B, Thymopentin and each the adjuvant equivalent mix homogeneously that progressively increases is surveyed intermediate content, and it is heavy to calculate sheet, dry powder direct tabletting, during tabletting the hardness of control strip at 3～7kgN, standby;
C, preparation coating materials carry out coating to the tablet that has suppressed, and the coating weightening finish is: 5～15mg/cm2, packing promptly.
The present invention also provides the purposes of oral Thymopentin enteric coated preparation in the immunoregulatory medicine of preparation.
Oral enteric preparation of the present invention solved well the thymopentin oral administration the time easily become aminoacid, little peptide and lose activity by the enzymatic degradation in gastric acid, the gastrointestinal; Be difficult for to see through gastrointestinal mucosa and bioavailability is very low; Liver has shortcomings such as first pass effect influence to oral Thymopentin.
To sum up, oral enteric preparation of the present invention can solve the problem of thymopentin oral administration, for having increased, Thymopentin gives new route of administration, prove by the test of pesticide effectiveness, medicine of the present invention has indication identical with injection and drug effect, for the utilization of clinical Thymopentin preparation provides a kind of new selection to increase patient's compliance.
Description of drawings
Fig. 1 embodiment 2 Thymopentin enteric coatel tablets release in vitro line chart of writing music;
Fig. 2 embodiment 6 Thymopentin enteric coated preparation release in vitro line chart of writing music;
The little micropill release in vitro of Fig. 3 embodiment 11 Thymopentin colon slowbreaks curve chart.
Obviously, according to foregoing of the present invention,,, can also make modification, replacement or the change of other various ways not breaking away under the above-mentioned basic fundamental thought of the present invention prerequisite according to the ordinary skill and the customary means of this area.
The specific embodiment of form is described in further detail foregoing of the present invention again by the following examples.But this should be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following example, all technology that realizes based on foregoing of the present invention all belong to scope of the present invention.
The specific embodiment
The preparation of embodiment 1 Thymopentin enteric coatel tablets of the present invention
(1) plain tablet recipe (per thousand consumptions):
Thymopentin 5g, NaTDC 10g, tristerin 30g, polyacrylic acid crosslinked polymer 10g, aprotinin 7g, microcrystalline Cellulose 100g, carboxymethyl starch sodium 10g, micropowder silica gel 10g, magnesium stearate 10g.
(2) coating materials prescription:
Pulvis Talci 20g, propylene glycol 20g, acrylic resin 60g.
(3) technology of Thymopentin enteric coatel tablets preparation
A, the Thymopentin of getting following weight proportion and adjuvant:
Thymopentin 5g, NaTDC 10g, tristerin 30g, polyacrylic acid crosslinked polymer 10g, aprotinin 7g, microcrystalline Cellulose 100g, carboxymethyl starch sodium 10g, micropowder silica gel 10g, magnesium stearate 10g cross the pharmacopeia sieve respectively No. 3, and be standby;
B, Thymopentin and each the adjuvant equivalent mix homogeneously that progressively increases is surveyed intermediate content, and it is heavy to calculate sheet, dry powder direct tabletting (during tabletting the hardness of control strip 3～7kgN), standby;
The enteric coating agents that c, usefulness prepare is carried out coating to the tablet that has suppressed, and the coating weightening finish is: 5～15mg/cm
2, packing promptly obtains Thymopentin enteric coatel tablets disclosed by the invention.
The preparation of embodiment 2 Thymopentin enteric coatel tablets of the present invention
(1) plain tablet recipe (per thousand consumptions):
Thymopentin 15g, sodium cholate 10g, tristerin 15g, polyacrylic acid crosslinked polymer 10g, pepsin inhibitor 15g, lactose 300g, sodium alginate 20g, micropowder silica gel 10g, magnesium stearate 10g.
(2) coating materials prescription:
Pulvis Talci 20g, propylene glycol 20g, acrylic resin 60g.
(3) technology of Thymopentin enteric coatel tablets preparation: with reference to embodiment 1.
The preparation of embodiment 3 Thymopentin enteric coatel tablets of the present invention
(1) plain tablet recipe (per thousand consumptions):
Thymopentin 50g, NaTDC 20g, tristerin 30g, polyacrylic acid crosslinked polymer 10g, sodium glycocholate 20g, mannitol 700g, low-substituted hydroxypropyl cellulose 50g, micropowder silica gel 10g, magnesium stearate 10g.
(2) coating materials prescription:
Pulvis Talci 20g, propylene glycol 20g, acrylic resin 60g.
(3) technology of Thymopentin enteric coatel tablets preparation: with reference to embodiment 1.
The preparation of embodiment 4 Thymopentin colon slowbreak sheets of the present invention
(1) plain tablet recipe (per thousand consumptions):
Thymopentin 30g, NaTDC 20g, tristerin 20g, polyacrylic acid crosslinked polymer 10g, aprotinin 15g, amylum pregelatinisatum 700g, crospolyvinylpyrrolidone 20g, micropowder silica gel 10g, magnesium stearate 10g.
(NaTDC, glyceryl stearate, polyacrylic acid crosslinked polymer can be as absorption enhancer, and three's consumption adds up in the absorbent amount ranges)
(2) coating materials prescription:
(3) technology of Thymopentin colon slowbreak sheet preparation: with reference to embodiment 1.
The preparation of embodiment 5 Thymopentin enteric coated capsulees of the present invention
(1) capsule 's content prescription (per thousand consumptions):
Thymopentin 15g, NaTDC 20g, tristerin 30g, polyacrylic acid crosslinked polymer 10g, aprotinin 20g, micropowder silica gel 10g, starch 700g.
(2) coating materials prescription:
Pulvis Talci 20g, propylene glycol 20g, acrylic resin 60g.
(3) technology of Thymopentin enteric coated capsule preparation
A, the Thymopentin of getting following weight proportion and adjuvant:
Thymopentin 10g, NaTDC 20g, tristerin 30g, polyacrylic acid crosslinked polymer 10g, aprotinin 20g, micropowder silica gel 10g, starch 700g;
B, Thymopentin and each the adjuvant equivalent mix homogeneously that progressively increases is surveyed intermediate content, calculates loading;
C, capsule 's content is filled in the capsule by the loading that calculates;
D, capsule is carried out enteric coating, the coating weightening finish is: 5～15mg/cm
2, packing promptly obtains Thymopentin enteric coated capsule disclosed by the invention.
The preparation of embodiment 6 Thymopentin enteric coated capsulees of the present invention
(1) capsule 's content prescription (per thousand consumptions):
Thymopentin 40g, NaTDC 20g, tristerin 30g, polyacrylic acid crosslinked polymer 10g, aprotinin 20g, hydroxypropyl emthylcellulose 5g.
(2) coating materials prescription:
Pulvis Talci 20g, propylene glycol 20g, acrylic resin 60g.
(3) technology of Thymopentin enteric coated capsule preparation: with reference to embodiment 5.
The preparation of embodiment 7 Thymopentin enteric pillers of the present invention (micropill)
(1) medicine layer prescription (per thousand preparation unit's consumptions)
Thymopentin 50g, NaTDC 20g, tristerin 30g, polyacrylic acid crosslinked polymer 10g, aprotinin 20g, hydroxypropyl emthylcellulose 5g.
(2) coating materials prescription:
Antiplastering aid 20g, plasticizer 20g, acrylic resin 60g.
(3) technology of Thymopentin enteric piller (micropill) preparation
A, the Thymopentin of getting following weight proportion and adjuvant:
Thymopentin 50g, NaTDC 20g, tristerin 30g, polyacrylic acid crosslinked polymer 10g, aprotinin 20g, hydroxypropyl emthylcellulose 5g.
B, with the above-mentioned g that respectively organizes with the dissolving of suitable quantity of water or certain density ethanol water, standby;
C, the blank pill heart is put in the fluid bed, the blank pill heart is carried out the medicine layer coating;
The medicament contg of medicine layer piller (micropill) has been wrapped in d, detection;
E, in fluid bed, above-mentioned piller is carried out enteric coating, promptly obtain Thymopentin enteric piller disclosed by the invention (micropill).
The preparation of embodiment 8 Thymopentin enteric coated capsulees of the present invention
Get the prepared Thymopentin enteric piller (micropill) of embodiment 7, need filled capsules, promptly obtain Thymopentin enteric coated capsule disclosed by the invention according to dosage.
The preparation of embodiment 9 Thymopentin enteric coatel tablets of the present invention
Get the prepared Thymopentin enteric piller (micropill) of embodiment 7, need carry out tabletting, promptly obtain Thymopentin enteric disclosed by the invention and release sheet according to dosage.
The capsular preparation of embodiment 10 Thymopentin colon slowbreaks of the present invention
(1) capsule 's content prescription (per thousand consumptions):
Thymopentin 30g, sodium cholate 20g, tristerin 30g, polyacrylic acid crosslinked polymer 10g, aprotinin 20g, micropowder silica gel 10g, starch 700g.
(2) coating materials prescription:
(3) technology of Thymopentin colon slowbreak capsule preparation: with reference to embodiment 5
The preparation of embodiment 11 Thymopentin colon slowbreak pillers of the present invention (micropill)
(1) medicine layer prescription (per thousand preparation unit's consumptions):
Thymopentin 15g, NaTDC 20g, tristerin 30g, polyacrylic acid crosslinked polymer 10g, aprotinin 20g, hydroxypropyl emthylcellulose 5g.
(2) coating materials prescription:
(3) technology of Thymopentin colon slowbreak piller (micropill) preparation: with reference to embodiment 7.
The capsular preparation of embodiment 12 Thymopentin colon slowbreaks of the present invention
Get the prepared Thymopentin colon slowbreak piller (micropill) of embodiment 11, need filled capsules, promptly obtain Thymopentin colon slowbreak capsule disclosed by the invention according to dosage.
Embodiment 13 Thymopentin colon slowbreaks of the present invention are released the preparation of sheet
Get the prepared Thymopentin colon slowbreak piller (micropill) of embodiment 11, need carry out tabletting, promptly obtain Thymopentin colon slowbreak disclosed by the invention and release sheet according to dosage.
The preparation of embodiment 14 Thymopentin colon slowbreak dry suspension of the present invention
Get the prepared Thymopentin colon slowbreak piller (micropill) of embodiment 11, it is carried out the waterproof coating, need pack, promptly obtain Thymopentin colon slowbreak dry suspension disclosed by the invention according to dosage.
The preparation of embodiment 15 Thymopentin enteric coated granules of the present invention
(1) granule prescription (per thousand preparation unit's consumptions):
Thymopentin 50g, NaTDC 20g, tristerin 30g, polyacrylic acid crosslinked polymer 10g, aprotinin 20g, micropowder silica gel 10g, starch 700g, binding agent 10～20g.
(2) coating materials prescription:
EUDRAGIT S 00 preparation solid content is 10% coating solution.Wherein antiplastering aid Talc accounts for 50% in the EUDRAGIT polymer, and plasticizer TEC accounts for 10%, and all the other are resin.
(3) technology of Thymopentin colon slowbreak granule preparation
A, the Thymopentin of getting following weight proportion and adjuvant:
Thymopentin 50g, NaTDC 20g, tristerin 30g, polyacrylic acid crosslinked polymer 10g, aprotinin 20g, micropowder silica gel 10g, starch 700g.
B, Thymopentin and each the adjuvant equivalent mix homogeneously that progressively increases adds binding agent and makes soft material, makes granule by 20～24 mesh standard sieves, oven dry, granulate.
C, granule is carried out the colon delayed release coat, the coating weightening finish is: 5～15mg/cm
2, survey intermediate content.
D, by the amount of calculating, pack according to taking dose and promptly to obtain Thymopentin colon slowbreak granule disclosed by the invention.
The preparation of embodiment 16 Thymopentin colon slowbreak powder of the present invention
(1) granule prescription (per thousand preparation unit's consumptions):
Thymopentin 50g, NaTDC 20g, tristerin 30g, polyacrylic acid crosslinked polymer 10g, aprotinin 20g, micropowder silica gel 10g, starch 700g, binding agent 10～20g.
(2) coating materials prescription:
(3) technology of Thymopentin colon slowbreak granule preparation
A, the Thymopentin of getting following weight proportion and adjuvant:
Thymopentin 50g, NaTDC 20g, tristerin 30g, polyacrylic acid crosslinked polymer 10g, aprotinin 20g, micropowder silica gel 10g, starch 700g.
B, Thymopentin and each the adjuvant equivalent mix homogeneously that progressively increases.
C, by fluid bed powder is carried out the colon delayed release coat, the coating weightening finish is: 5～15mg/cm
2, survey intermediate content.
D, by the amount of calculating, pack according to taking dose and promptly to obtain Thymopentin colon slowbreak powder disclosed by the invention.
The capsular preparation of embodiment 17 Thymopentin colon slowbreaks of the present invention
Get the prepared Thymopentin colon slowbreak powder of embodiment 16, need filled capsules, promptly obtain Thymopentin colon slowbreak capsule disclosed by the invention according to dosage.
The preparation of embodiment 18 Thymopentin colon slowbreak sheets of the present invention
Get the prepared Thymopentin colon slowbreak powder of embodiment 16, need carry out tabletting, promptly obtain Thymopentin colon slowbreak disclosed by the invention and release sheet according to dosage.
Embodiment 19 Thymopentin colon slowbreaks of the present invention are released the preparation of sheet
Get the prepared Thymopentin colon slowbreak powder of embodiment 16, powder is carried out the waterproof coating, need pack, promptly obtain Thymopentin colon slowbreak dry suspension disclosed by the invention according to dosage by fluid bed.
Below by concrete physics and chemistry evidence beneficial effect of the present invention.
The present invention increases weight the position and the time of control drug release by coating, so the coating weightening finish has certain influence to assimilation effect of the present invention, determines the scope that coating increases weight below by experiment.
Sample thief is an amount of, uses the coating solution for preparing to its coating that carries out different weightening finishes, then sample is carried out drug release determination under different pH value environment, and result's demonstration is worked as the coating weightening finish less than 5mg/cm
2The time, sample idol in the environment of pH value 1 has a small amount of release, and part begins to discharge in the environment of pH value 2～4, discharges rapidly in pH value 5～8 environment, and coating increases weight greater than 15mg/cm
2The time sample in pH value 1～7 environment, do not have to discharge in 2 hours, in pH value 7.8～8.0 environment, do not have in 1 hour and discharge.When coating increases weight at 5～15mg/cm
2The time, sample 2 hours nothings in the environment of pH value 1 discharge, and do not have release in 2 hours in pH value 2～6.8 environment, discharge rapidly in pH value 7.8～8.0 environment.Therefore in conjunction with absorption site pH value feature of the present invention, selecting the coating weightening finish is 5～15mg/cm
2
Embodiment 21 medicine release in vitro degree tests of the present invention
The preparation of embodiment 1-19 preparation is carried out through release in vitro degree verification experimental verification, all can reach the regulation of 2005 editions enteric coated preparation of Chinese Pharmacopoeia and slowbreak preparation.
Following is each preparation release in vitro degree result of the test of preparation:
Table 1 Thymopentin enteric coated preparation (embodiment 1-19) release in vitro degree result of the test
| pH＝1 | pH＝7.0 | ||||
| |
0 |
120 minutes | 125 |
130 |
140 |
| Dissolution | |||||
| 0 | 0 | 10～20％ | 50～70％ | 80～100％ | |
By above data as can be seen, this product is stable in 2 hours in the 0.1mol/L hydrochloric acid solution, discharges (see figure 1) in the phosphate buffer of pH7.0 in 20 minutes substantially fully.
Table 2 Thymopentin enteric coated preparation (embodiment 1-19) release in vitro degree result of the test 1 (see figure 2)
| pH＝1 | pH＝6.8 | ||||
| |
0 |
120 |
180 |
240 |
300 |
| Dissolution | |||||
| 0 | 0 | 0 | ＜10％ | 20～40％ | |
Table 3 Thymopentin enteric coated preparation (embodiment 1-19) release in vitro degree result of the test 2 (see figure 3)s
| pH＝1 | pH＝7.8～8.0 | ||||
| |
0 |
120 |
180 minutes | 210 |
240 |
| Dissolution | |||||
| 0 | 0 | 0 | 60～80％ | ＞90％ | |
By above data and figure, as can be seen, medicine of the present invention does not have release in 2 hours in the 0.1mol/L hydrochloric acid solution, does not have in 1 hour to discharge in the phosphate buffer of pH6.8, only discharges 3.05%, 2 hour and discharges 30.5% in 1.5 hours; In the phosphate buffer of pH7.8～8.0, do not have in 1 hour and discharge release in 1.5 hours release fully in 86%, 2 hour.
Below beneficial effect by pharmacodynamics test proof medicine of the present invention.
The 1 medicine effect test of the present invention of test example
By normal dogs and two kinds of models of preparation immunologic hypofunction dog, measure 2 pairs of dog peripheral bloods of embodiment of the invention CD4T lymphocyte (being called for short CD4), CD8T lymphocyte (being called for short CD8), CD4/CD8 and lymphocyte transformation ability, positive group is selected thymopentin for injection (tp-5) for use.
Table 4 the present invention is to the influence of normal dogs t lymphocyte subsets of peripheral blood
| Group | Dosage | CD4 | CD8 | CD4/CD8 |
| Blank group | - | 40.99±4.05 | 20.12±3.15 | 2.08±0.35 |
| The present invention | 5mg/ only | 42.46±5.51 | 18.86±2.79 | 2.31±0.50 |
| 2mg/ only | 41.92±5.39 | 19.92±2.83 | 2.20±0.43 | |
| Positive group | 0.36mg/ only | 44.32±5.71 | 17.93±3.15 | 2.60±0.82 * |
Annotate: compare * P＜0.05 with the blank group
Table 5 the present invention is to the influence of dog lymphocyte transformation function
| Group | Dosage | Lymhocyte transformation rate (%) | |
| The L-asparaginase | Thymopentin | ||
| Blank group | - | - | 129.5±17.72 ** |
| Model group | 400u/kg | - | 108.67±10.76 |
| The present invention | 400u/kg | 5mg/ only | 113.33±25.24 |
| 400u/kg | 2mg/ only | 110.53±18.73 | |
| Positive group | 400u/kg | 0.36mg/ only | 122.83±9.53 * |
Annotate: compare * * P＜0.01, *＜0.05 with model group
Table 6 the present invention is to dog t lymphocyte subset group's influence
| Group | Dosage | CD4 | CD8 | CD4/CD8 | |
| The L-asparaginase | Thymopentin | ||||
| Blank group | - | - | 41.37± 4.58 ** | 20.39± 3.03 ** | 2.07±0.35 ** |
| Model group | 400u/kg | - | 35.33±7.01 | 26.03±3.55 | 1.37±0.32 |
| The present invention | 400u/kg | 5mg/ only | 37.45±3.07 | 22.36± 2.50 ** | 1.69±0.22 ** |
| 400u/kg | 2mg/ only | 36.41±2.96 | 23.69±2.68 | 1.53±0.25 | |
| Positive group | 400u/kg | 0.36mg/ only | 37.17±3.61 | 21.08± 3.15 ** | 1.88±0.23 ** |
Annotate: compare * * P＜0.01 with model group
Experimental result shows: model group and blank group compare, and lymphocyte transformation ability, CD4, CD4/CD8 all significantly reduce; CD8 significantly raises, and shows that the immunomodulating of L-asparaginase group canine cells strengthens relatively, immunologic function degression, and promptly intravenous injection L-asparaginase can cause dog immunocompromised model.And positive drug group (thymopentin for injection (tp-5)) and model group are relatively, lymphocyte transformation ability, CD4/CD8 significantly rise, CD8 significantly descends, but show the dog immunocompromised effect that thymopentin for injection (tp-5) antagonism L-asparaginase causes, and have the forward immunoregulation effect; For normal beagle dog, thymopentin for injection (tp-5) has certain immunological enhancement equally.And the present invention all has and the identical pharmacological action of positive drug (thymopentin for injection (tp-5)) from above experimental result, when dosage of the present invention is 5-15 a times of positive drug, demonstrates similar immunoregulation effect.Because safety non-toxic during thymopentin oral, according to thymopentin for injection (tp-5) dosage (1mg/ preparation unit and 10mg/ preparation unit), the every preparation unit dose of the present invention is decided to be 5～150mg/ preparation unit.The further preferable range of Thymopentin consumption is 15～30mg/ unit, preliminary test proves according to pharmacodynamics, when being 15 times of injection, the thymopentin oral consumption shows immunological enhancement, the dosage of injection is 1mg/ unit, when 1～2 times of consumption, show the immunological enhancement optimum, therefore preferred oral dosage is 15～30 times of injection, i.e. 15～30mg/ unit.
Above-mentioned pharmacodynamics test explanation, medicine of the present invention has indication identical with injection and drug effect, well solved the problem of thymopentin oral administration, for having increased, Thymopentin gives new route of administration, increased patient's compliance, for the utilization of clinical Thymopentin preparation provides a kind of new selection.
Claims (15)
1. oral Thymopentin enteric coated preparation is characterized in that: it is that Thymopentin by effective dose is an active component, adds the oral enteric preparation that acceptable accessories is prepared from, and Thymopentin 5～150mg is contained in every preparation unit.
2. oral Thymopentin enteric coated preparation according to claim 1, it is characterized in that: every preparation unit contains Thymopentin 15～50mg.
3. according to claim 1 or 2 described oral Thymopentin enteric coated preparation, it is characterized in that: the adjuvant that contains the following weight proportioning: 5～100 parts of absorption enhancers, 7～70 parts of enzyme inhibitors, 5～15 parts of coating materials.
4. oral Thymopentin enteric coated preparation according to claim 3 is characterized in that: described absorption enhancer is one or more in tristerin, polyacrylic acid crosslinked polymer, fatty acid, cholic acid, deoxycholic acid and its esters; Described enzyme inhibitor is for pressing down in enzyme peptide aprotinin, aprotinin, pepsin inhibitor, sodium glycocholate, camostat mesilate camostat mesilate, bacitracin bacitracin, the Semen sojae atricolor pancreatin inhibitor etc. one or more.
5. oral Thymopentin enteric coated preparation according to claim 3 is characterized in that: described coating materials is the adjuvant that contains the following weight proportioning: 1～5 part of antiplastering aid, 0.4～3 part of plasticizer, 3.6～7 parts of enteric solubility adjuvants.
6. oral Thymopentin enteric coated preparation according to claim 5 is characterized in that: described antiplastering aid is one or more in Pulvis Talci, magnesium stearate, the micropowder silica gel; Plasticizer is one or more in propylene glycol, glycerol, Polyethylene Glycol, glycerol triethyl, triethyl citrate, acetyl monoglyceride, phthalate, the Oleum Ricini; The enteric solubility adjuvant is one or more in crylic acid resin, hydroxypropyl cellulose class, arabic gum, the Lac.
7. according to claim 3,4 described oral Thymopentin enteric coated preparation, it is characterized in that: described enteric coated preparation also comprises the adjuvant of following weight proportioning:
7～700 parts of filleies, 0～100 part of disintegrating agent, 0～10 part of lubricant, 0～10 part of fluidizer.
8. oral Thymopentin enteric coated preparation according to claim 7 is characterized in that: described filler is one or more in microcrystalline Cellulose, mannitol, lactose, the amylum pregelatinisatum; Described disintegrating agent is one or more in crospolyvinylpyrrolidone, low-substituted hydroxypropyl cellulose, carboxymethyl starch sodium, microcrystalline Cellulose, the sodium alginate; Described lubricant, fluidizer are one or more in Pulvis Talci, micropowder silica gel, hydrogenated vegetable oil, Polyethylene Glycol, stearic acid, magnesium stearate, the dicalcium phosphate dihydrate.
9. according to each described oral Thymopentin enteric coated preparation of claim 1-8, it is characterized in that: described preparation is tablet, capsule, pilule, pellet, granule, dry suspension, suspensoid.
10. oral Thymopentin enteric coated preparation according to claim 9 is characterized in that: described tablet is enteric coatel tablets, and it is that the Thymopentin and the adjuvant that contain the following weight proportioning are prepared from:
15～50 parts of Thymopentin, 5～30 parts of NaTDCs, 15～30 parts of tristerins, 10～20 parts in polyacrylic acid crosslinked polymer, 7～70 parts of aprotiniies, 10～700 parts of amylum pregelatinisatums, 20～100 parts of crospolyvinylpyrrolidone, 2～10 parts of micropowder silica gels, 2～10 parts of magnesium stearate, 5～15 parts of coating materials.
11. oral Thymopentin enteric coated preparation according to claim 10 is characterized in that: it is that the Thymopentin and the adjuvant that contain the following weight proportioning are prepared from:
5 parts of Thymopentin, 10 parts of NaTDCs, 30 parts of tristerins, 10～20 parts in polyacrylic acid crosslinked polymer, 7 parts of aprotiniies, 700 parts of amylum pregelatinisatums, 20 parts of crospolyvinylpyrrolidone, 10 parts of micropowder silica gels, 10 parts of magnesium stearate, 5～15 parts of coating materials.
12. oral Thymopentin enteric coated preparation according to claim 11 is characterized in that: it is prepared from by the Thymopentin and the adjuvant of following weight proportioning:
5 parts of Thymopentin, 10 parts of NaTDCs, 30 parts of tristerins, 10～20 parts in polyacrylic acid crosslinked polymer, 7 parts of aprotiniies, 700 parts of amylum pregelatinisatums, 20 parts of crospolyvinylpyrrolidone, 10 parts of micropowder silica gels, 10 parts of magnesium stearate, 5～15 parts of coating materials.
13. as each described oral Thymopentin enteric coated preparation of claim 10-12, it is characterized in that: weightening finish is behind the coating: 5～15mg/cm
2, enteric coated tablet hardness be 3～7kgN.
14. preparation method for preparing each described oral Thymopentin enteric coated preparation of claim 10-13, it is to be active component with the Thymopentin, add absorption enhancer, enzyme inhibitor, be pressed into plain sheet, by the enteric coated enteric coatel tablets that are prepared into of coating materials, comprise following concrete steps again:
A, the Thymopentin that takes by weighing following weight proportion and adjuvant:
5～50 parts of Thymopentin, 5～100 parts of absorption enhancers, 7～70 parts of enzyme inhibitors, 10～700 parts of filleies, 0～100 part of disintegrating agent, 0～10 part of lubricant, 0～10 part of fluidizer are crossed the pharmacopeia sieve respectively No. 3, and be standby;
B, Thymopentin and each the adjuvant equivalent mix homogeneously that progressively increases is surveyed intermediate content, and it is heavy to calculate sheet, dry powder direct tabletting, during tabletting the hardness of control strip at 3～7kgN, standby;
C, preparation coating materials carry out coating to the tablet that has suppressed, and the coating weightening finish is: 5～15mg/cm2, packing promptly.
15. the purposes of each described oral Thymopentin enteric coated preparation of claim 1-13 in the immunoregulatory medicine of preparation.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105288583A (en) * | 2015-11-13 | 2016-02-03 | 海南森瑞谱生命科学药业股份有限公司 | Oral thymopentin preparation and preparation method thereof |
| CN105709208A (en) * | 2016-01-29 | 2016-06-29 | 陕西科技大学 | Preparation technology of bitter gourd protein enteric-coated tablets |
| CN109575100A (en) * | 2018-10-25 | 2019-04-05 | 大连大学 | Glycocholic acid application in preparation of anti-tumor drugs |
| 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 |
| CN113121648A (en) * | 2015-06-02 | 2021-07-16 | 河北科技大学 | N-methyl cyclic pentapeptide compound and synthesis method and application thereof |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1714861B (en) * | 2004-06-28 | 2012-10-10 | 中国医学科学院药物研究所 | Thymus penta peptide slow releasing micro ball and its preparing method |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN113121648A (en) * | 2015-06-02 | 2021-07-16 | 河北科技大学 | N-methyl cyclic pentapeptide compound and synthesis method and application thereof |
| CN113121648B (en) * | 2015-06-02 | 2022-07-01 | 河北科技大学 | N-methyl cyclic pentapeptide compound and synthesis method and application thereof |
| CN105288583A (en) * | 2015-11-13 | 2016-02-03 | 海南森瑞谱生命科学药业股份有限公司 | Oral thymopentin preparation and preparation method thereof |
| CN105709208A (en) * | 2016-01-29 | 2016-06-29 | 陕西科技大学 | Preparation technology of bitter gourd protein enteric-coated tablets |
| CN109575100A (en) * | 2018-10-25 | 2019-04-05 | 大连大学 | Glycocholic acid application in preparation of anti-tumor drugs |
| 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 |
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| CN101108246B (en) | 2013-03-06 |
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