CN105288583A - Oral thymopentin preparation and preparation method thereof - Google Patents

Abstract

The invention discloses an oral thymopentin preparation and a preparation method thereof. The oral thymopentin preparation is prepared from thymopentin, sodium alginate, calcium chloride, polyethylene glycol, an absorption promoter and an enzyme inhibitor. The invention also provides a preparation method of the oral thymopentin preparation. Thymopentin microsphere is prepared from thymopentin so that biological stability is improved and effects of resisting gastric acid and enzyme degradation are obtained. The oral thymopentin preparation is suitable for oral administration so that long-term frequent injection-caused patient pain and inconvenience are avoided and a good clinical application prospect is obtained.

Description

A kind of oral Thymopentin preparation and preparation method thereof

Technical field

The present invention relates to field of medicaments, particularly relate to a kind of oral Thymopentin preparation and preparation method thereof.

Background technology

Thymopentin (thymopentin, TP-5) is the pentapeptide of synthetic, is made up of arginine, lysine, aspartic acid, valine, tyrosine five seed amino acid.Thymopentin and thymopoietin II (ThymopoietinII, the pentapeptide fragment (32-36 amino acids) at immunocompetence center TP-II) is identical, there are the whole physiological functions identical with thymopoietin II, there is immune dual regulation.Thymopentin is mainly used in treating the auxiliary treatment etc. of the low disease of chronic hepatitis, various constitutional or Secondary cases T cell deficiency disorders, some autoimmune disease, various cellular immune function and malignant tumor clinically.

Thymopentin is peptide medicament, easily by gastric acid and gastrointestinal proteasome degradation, oral invalid, and therefore, the main path of the current clinical administration of Thymopentin is vein or subcutaneous injection.Thymopentin is easily degraded to aminoacid by protease and aminopeptidase in blood, and the half-life only has about 30 seconds, need every day or the next day administration, the patient that is administered to of long term frequent brings a lot of painful and inconvenient, and compliance is poor, and can produce many untoward reaction.

Alginic acid (Alginicacid) is a kind of acidic polysaccharose extracted from Brown algae, the linear macromolecular compound be made up of β-D-manna aldehydic acid (M) and α-L-guluronic acid (G), carboxyl and hydroxyl is freely contained in its molecule, can react with polyvalent metal ion and form slightly solubility gel, the calcium alginate such as formed with calcium, be suitable for embedding protein, enzyme and cell isoreactivity material, there is good biocompatibility and bioadhesive, can be used as slow (control) release formulation carrier of oral drugs, gastric acid and enzyme can be prevented the Degradation of medicine, improve the stability of peptide and protein drugs, the intestinal absorption of effective promotion peptide and protein drugs, improve the bioavailability of medicine.

Oral administration compliance is good, is current optimal Non-injective route, therefore, develops a kind of novel oral Thymopentin preparation and has great potential applicability in clinical practice.

Summary of the invention

The object of this invention is to provide a kind of oral Thymopentin preparation, oral Thymopentin preparation can resist the Degradation of gastric acid and enzyme preferably, can be taken orally, and avoids long term frequent and is administered to the misery and inconvenience that patient brings.

To achieve these goals, technical scheme of the present invention is: provide a kind of oral Thymopentin preparation, wherein, Thymopentin and Polyethylene Glycol are added stirring and evenly mixing in sodium alginate soln, obtain after mixed liquor being instilled in calcium chloride solution Thymopentin microsphere adds absorption enhancer, enzyme inhibitor is prepared from; The weight ratio of described Thymopentin, Polyethylene Glycol and sodium alginate is 1:1 ~ 10:5 ~ 20.

Another object of the present invention is to the preparation method that a kind of oral Thymopentin preparation is provided, comprise the following steps:

(1) compound concentration is 10 ~ 30mg/ml sodium alginate soln;

(2) take Thymopentin and Polyethylene Glycol adds in sodium alginate soln, stir, make it fully mix, obtain mixed liquor; The weight ratio of Thymopentin, Polyethylene Glycol and sodium alginate is 1:1 ~ 10:5 ~ 20;

(3) mixed liquor obtained in step (2) being instilled concentration is in 10 ~ 50mg/ml calcium chloride solution, the volume ratio of mixed liquor and calcium chloride solution is 1:20 ~ 100, after gentle agitation 1 ~ 5h, filter, after the microsphere distilled water wash of formation, adding concentration is that 3% Osmitrol disperses again, pre-freeze 24h at being placed in subzero 20 ~ 30 DEG C, more namely obtains Thymopentin microsphere through vacuum lyophilization 24 ~ 48h;

(4) adding absorption enhancer, enzyme inhibitor and customary adjuvant by obtaining Thymopentin microsphere in step (3), adopting conventional method to make tablet, capsule, pilule, pellet, powder, dry suspension, suspensoid.

Described Polyethylene Glycol is PEG3350, PEG4000, PEG6000, is conducive to the homogeneous formation of Thymopentin microsphere, avoids medicine carrying uneven, increases the stability of Thymopentin, and promotes that it absorbs.

Detailed description of the invention

Embodiment 1

Take 2g sodium alginate, 0.4g Thymopentin, 1gPEG3350, after dissolving with distilled water respectively, mixing and stirring, standardize solution 100ml.100ml mixed liquor being instilled under agitation concentration is in the calcium chloride solution of 20mg/ml, after reaction 1h, filters, collect microsphere, after distilled water wash, with concentration be 3% mannitol solution resuspended, be placed in subzero 20 DEG C of pre-freeze 24h, namely obtain Thymopentin microsphere through vacuum lyophilization 48h; Add NaTDC 60mg, aprotinin 10mg, adopt conventional method to make powder.

Embodiment 2

Take 1g sodium alginate, 0.1g Thymopentin, 0.5gPEG4000, after dissolving with distilled water respectively, mixing and stirring, standardize solution 100ml.100ml mixed liquor being instilled under agitation concentration is in the calcium chloride solution of 15mg/ml, after reaction 0.5h, filter, collect microsphere, after distilled water wash, with concentration be 3% mannitol solution resuspended, be placed in subzero 30 DEG C of pre-freeze 24h, namely obtain Thymopentin microsphere through vacuum lyophilization 48h; Add NaTDC 60mg, aprotinin 10mg, adopt conventional method to make capsule.

Embodiment 3

Take 2g sodium alginate, 0.1g Thymopentin, 1gPEG6000, after dissolving with distilled water respectively, mixing and stirring, standardize solution 100ml.100ml mixed liquor being instilled under agitation concentration is in the calcium chloride solution of 25mg/ml, after reaction 2h, filters, collect microsphere, after distilled water wash, with concentration be 3% mannitol solution resuspended, be placed in subzero 20 DEG C of pre-freeze 24h, namely obtain Thymopentin microsphere through vacuum lyophilization 48h; Add NaTDC 60mg, aprotinin 10mg, adopt conventional method to make tablet.

The Pharmacodynamic laboratory observation of oral Thymopentin

With the oral Thymopentin powder made by above-described embodiment 1, affect experiment and the cyclophosphamide that carry out the delayed allergy of dinitrofluorobenzene inducing mouse cause the low impact experiment of immune function of mice.Specific as follows:

(1) oral Thymopentin (TP-5) is on the impact of dinitrofluorobenzene inducing mouse delayed allergy

Experiment purpose: study the impact of oral TP-5 preparation on the mice delayed allergy that dinitrofluorobenzene (DNFB) is induced, investigates its regulating action to specific cellular immunity function.

Laboratory animal and reagent: kunming mice, male, 18 ~ 22g, by body weight random packet, often organizes 10.D.2,4-dinitrofluorobenzene (DNFB) solution D NFB50mg, adds freshly prepared acetone sesame oil solution (acetone: Oleum Sesami=1:1) 5ml, mixes for subsequent use.

Experimental technique: mice is divided into matched group, model group, blank control sample group, oral TP-5 preparation group (5mg/kg at random; 10mg/kg; 20mg/kg) with TP-5 injection group (subcutaneous 1mg/kg).Blank control sample group and oral TP-5 preparation group oral administration every other day, altogether administration 7 times.TP-5 injection group subcutaneous injection, administration every other day, altogether administration 7 times.Except matched group, each group mice after 2 days, scrapes off the hair of abdominal part in administration, area about 3 × 3cm2 size, uniform application DNFB solution 50 μ l sensitization, and strengthening next day once.After sensitization the 5th day, each group mice left ear uniform application DNFB solution 10 μ l attacked.Put to death animal after 24 hours, cut ears, sweep away left and right auricle with rustless steel blunderbuss that diameter is 8mm, weigh respectively, using the difference of left and right auricle weight as swelling degree.Get mouse thymus and spleen is weighed simultaneously, respectively using the spleen of the every 10g body weight of mice heavy (mg) and chest gland weight (mg) as index and spleen index and thymus index, add up the difference of each group.

Result: oral TP-5 preparation oral administration under 10mg/kg and 20mg/kg dosage has obvious potentiation to the mice ear that DNFB induces, and its increment rate is respectively 115.2% and 57.6%.Blank control sample on mice ear without impact.Oral TP-5 preparation is pointed out to have the effect obviously strengthening cellular immune function.

The oral TP-5 preparation of table 1. to the effect of the mice delayed allergy that DNFB induces (n=10, )

P<0.001, compares with matched group.

P<0.05, P<0.01, compare with model group.

(2) oral Thymopentin (TP-5) preparation causes the low impact of immune function of mice to cyclophosphamide

Experiment purpose: investigate oral TP-5 preparation and the low impact of immune function of mice is caused on cyclophosphamide, evaluate its immunoregulation effect.

Laboratory animal: Kunming mouse, male, 16 ~ 18g, by body weight random packet, often organizes 10.

Experimental technique: mice is divided at random oral TP-5 preparation group (5mg/kg; 10mg/kg; 20mg/kg), TP-5 injection group (subcutaneous 1mg/kg), blank control sample group, cyclophosphamide model group and normal group.Oral TP-5 preparation group and blank control sample group oral administration, every other day once, totally 7 times.TP-5 injection group subcutaneous administrations, 1 time every other day, totally 7 times.After administration terminates, except normal group, respectively group mice was administration the 9th day, intraperitoneal injection of cyclophosphamide 30mg/kg, every day 1 time, for three days on end.Blood is got in cyclophosphamide injection 6 days posterior orbits, leukocyte counts, gets mouse thymus and spleen simultaneously, weighs, using the spleen of the every 10g body weight of mice heavy (mg) and chest gland weight (mg) as index and spleen index and thymus index, and carry out statistical procedures.

Result: obviously can increase cyclophosphamide after the oral TP-5 preparation 5,10 of various dose and 20mg/kg administration 7 times and cause leukocyte count in immunologic hypofunction Mouse Blood, its increment rate is respectively 44%, 50% and 38%, has obviously learn difference with cyclophosphamide model group.Point out oral TP-5 preparation to have under dosage 5,10 and 20mg/kg and strengthen the effect that cyclophosphamide causes the immunologic function of immunologic hypofunction mice.

Table 2. oral TP-5 preparation on cyclophosphamide cause the low impact of immune function of mice (n=10, )

P<0.001, compares with normal group

P<0.05, compares with cyclophosphamide model group.

Conclusion: oral TP-5 preparation has the effect strengthening cyclophosphamide and cause the immunologic function of immunologic hypofunction mice when dosage 5mg/kg, and obviously can strengthen the effect of cellular immune function, suitable and subcutaneous injection TP-5 injection group (1mg/kg).

Above-mentioned pharmacodynamics test explanation, medicine of the present invention (oral TP-5 preparation) is effectively oral, there is the effect strengthening cyclophosphamide and cause the immunologic function of immunologic hypofunction mice, and obviously can strengthen the effect of cellular immune function, suitable with the subcutaneous injection of TP-5 injection.The present invention is directed to current Thymopentin and can only take drug administration by injection defect, provide a kind of new oral administration route, avoid misery and inconvenience that patient bears because of long term injections administration.Meanwhile, medicine of the present invention is easy to preserve, and does not need, as TP-5 injection low temperature or freezen protective, at room temperature to preserve.

Above disclosedly be only preferred embodiment of the present invention, certainly can not limit the interest field of the present invention with this, therefore according to the equivalent variations that the claims in the present invention are done, still belong to the scope that the present invention is contained.

Claims (3)

1. an oral Thymopentin preparation, it is characterized in that: Thymopentin and Polyethylene Glycol are added stirring and evenly mixing in sodium alginate soln, obtain after mixed liquor being instilled in calcium chloride solution Thymopentin microsphere adds absorption enhancer, enzyme inhibitor is prepared from; The weight ratio of described Thymopentin, Polyethylene Glycol and sodium alginate is 1:1 ~ 10:5 ~ 20.

2. the preparation method of oral Thymopentin preparation as claimed in claim 1, is characterized in that: comprise the following steps:

(1) compound concentration is 10 ~ 30mg/ml sodium alginate soln;

(2) take Thymopentin and Polyethylene Glycol adds in sodium alginate soln, stir, make it fully mix, obtain mixed liquor; The weight ratio of Thymopentin, Polyethylene Glycol and sodium alginate is 1:1 ~ 10:5 ~ 20;

(3) mixed liquor obtained in step (2) being instilled concentration is in 10 ~ 50mg/ml calcium chloride solution, the volume ratio of mixed liquor and calcium chloride solution is 1:20 ~ 100, after gentle agitation 1 ~ 5h, filter, after the microsphere distilled water wash of formation, adding concentration is that 3% Osmitrol disperses again, pre-freeze 24h at being placed in subzero 20 ~ 30 DEG C, more namely obtains Thymopentin microsphere through vacuum lyophilization 24 ~ 48h;

(4) adding absorption enhancer, enzyme inhibitor and customary adjuvant by obtaining Thymopentin microsphere in step (3), adopting conventional method to make tablet, capsule, pilule, pellet, powder, dry suspension, suspensoid.

3. oral Thymopentin preparation as claimed in claim 1, is characterized in that: described Polyethylene Glycol is PEG3350 or PEG4000 or PEG6000.