CN1853718A - Positioning composition for oral liquid and its preparation - Google Patents
Positioning composition for oral liquid and its preparation Download PDFInfo
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- CN1853718A CN1853718A CN 200510064708 CN200510064708A CN1853718A CN 1853718 A CN1853718 A CN 1853718A CN 200510064708 CN200510064708 CN 200510064708 CN 200510064708 A CN200510064708 A CN 200510064708A CN 1853718 A CN1853718 A CN 1853718A
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- thymosin alpha
- preparation
- oral
- enteric
- microsphere
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Abstract
An orally taken medicinal composition of thymosin alpha 1 carried by microspheres features that it can be located in intestinal tract to release the thymosin alpha 1. It is prepared from thymosin alpha 1, acrylic resin as enteric material, polyoxyvinyl laurinol ether and laury azazole ketone.
Description
Technical field:
The present invention relates to field of medicaments, a kind of Thymosin alpha that is
1Novel form---the enteric-coated microsphere preparation promptly is positioned preparation that small intestinal discharges and preparation method thereof.
Background technology:
Extrasin alpha
1(thymosin is called for short T α
1) be a kind of polypeptide with immunologic function, clinically viral hepatitis that are used for the treatment of more, its aminoacid sequence is-Ser-Asp-Ala-Ala-Val-Asp-Thr-Ser-Ser-Glu-Ile-Thr-Thr-Lys-Asp-Leu-Lys-Glu-Lys-Lys-Glu-Val-Val-Glu-Glu-Ala-Glu-Asn-[Glodstein AL, Low TL, McAdoo M, McClure J, et al.Thymosin alpha1:isolation and sequence analysis of an immunological active thymic peptide.Proc Natl Acad SciUSA, 1977,74 (2): 725～729].Present T α
1Have only a kind of dosage form---powder ampoule agent for injection, route of administration is single, is subcutaneous injection, and because of the reason of stable aspect, to having relatively high expectations in storage requirement and the use.
Because T α
1Indication be hepatitis, malignant tumor, immune deficiency disorder etc., the medication cycle is longer, this makes troubles not only for patient's life-time service but also brings unnecessary misery to the patient.So T α
1Oral formulations be needs very.
Have not yet to see T α
1The patent of oral formulations or patent application.
Chinese patent (number of patent application 02136181.9, Granted publication CN1176718C) has disclosed T α
1Microball preparation and preparation method thereof, it adopts emulsifying agent Tween80 or Span80 and 3～5mg T α
1Be emulsifiable in the dichloromethane solution that 10ml contains 5～20%PLGA, temperature is 15 ± 2 ℃, T α
1Emulsion; Under stirring condition the Emulsion for preparing slowly splashed in the aqueous solution that contains 0.5～10% PVA, stir 10min, speed is 300～1000rpm, and impouring 500ml distilled water in this system continues to stir again, organic solvent is volatilized form the pastille microsphere.The embodiment that this patent proposes uses the Xiao Bai pig, has set up dark II ° scalding model, uses T α
1The wound healing of microsphere more not user is faster.
Summary of the invention:
Protein and polypeptide drug oral administration need solve two problems, the one, stability problem, because medicine at first enters in the stomach after oral, protein and polypeptide drug are difficult to bear the strong acidic environment of gastric juice, and also contain other enzymes of existing in pepsin and the digestive tract in the gastric juice protein is produced the degraded destruction; The inventor is with T α
1Make enteric-coated microsphere, insoluble under one's belt, enter the T α in the intestinal microsphere
1Stripping can avoid gastric acid and pepsin to T α
1Destruction; In addition, add hyaluronidase in prescription, the hydrolysis hyaluronic acid reduces hyaluronic acid and stops the diffusion of exotic in tissue, and the density of mucosa is reduced; Because of the molecular weight of polypeptide drugs is bigger, exist the barrier action of gastrointestinal tract cell, adding absorption enhancer can address this problem.
One, reagent, material and instrument
D25-2 type motor stirrer, Hangzhou motor for instrument factory;
7901 type electromagnetism bench mixer Shanghai brilliance instrument and meter factories
Acrylic resin II number: pharmaceutical grade, Lianyun Harbour system iodine factory
Phthalic acid hypromellose ester: pharmaceutical grade, Japanese SHIN-ETSU HANTOTAI (Shin-Etsu Chemical Co., Ltd)
T α
1Standard substance are available from Italian ISFS.P.A. company, and gelatin, Fu Shi Freund's complete adjuvant be available from Sigma company, the biotin mark
The goat anti-rabbit igg of note is a Catalog company product
Hyaluronidase: Sigma company
Gelatin: Qinghai gelatin limited company
Brij30: analytical pure, Ubichem company
Laurocapram: analytical pure, Hubei Rhizoma Arisaematis chemical general factory
Sodium cholate: pharmaceutical grade, due east, Sichuan Pharmaceutical Co
Lecithin: pharmaceutical grade, the prosperous Wei Ge in Heilungkiang pharmaceutcal corporation, Ltd
Fabaceous lecithin: pharmaceutical grade, Jinban Pharmaceutical Co., Ltd., Shanghai
Polyvidone series: pharmaceutical grade, BASF AG
Linoleic acid: pharmaceutical grade, HARBIN PHARMACEUTICAL GROUP CO., LTD. General Pharm. Factory
Benzyl alcohol: pharmaceutical grade, Xuzhou zero diopter Pharmaceutical Co
Ethanol: analytical pure, Beijing chemical reagents corporation
Two, the preparation of microsphere and detection method
1. the basic preparation method of microsphere
Precision takes by weighing T α
1Be dissolved in right amount in the phosphate buffer of 0.1mol/L, precision takes by weighing acrylic resin II number and other compositions are dissolved in the ethanol in right amount, with two kinds of solution mixings, under high-speed stirred, be scattered in the liquid paraffin again, slowly add gelatin solution, be stirred to microsphere and solidify centrifugal collecting precipitation, remove the liquid paraffin on surface with petroleum ether, drying under reduced pressure 12h promptly.To the microsphere of preparing, adopt the mode of appearance of observation by light microscope microsphere.
2. the mensuration of microsphere capacity antacid
Take by weighing two parts of T α
1Each 0.1g of enteric-coated microsphere, a its content of dispersion of measuring, another part stirs 2h in 37 ℃ of 200ml simulated gastric fluids, centrifugal, and taking precipitate is measured T α wherein
1The reservation amount, and under optical microscope, observe the metamorphosis of microsphere, repeat 3 times.Concrete assay method slightly.
3. microsphere enteric ability is investigated
Take by weighing two parts of T α
1Each 0.1g of enteric-coated microsphere, a its content of dispersion of measuring of radiation, another part stirs 1h in 37 ℃ of 200ml simulated intestinal fluids, measure the T α in the solution
1Amount is calculated T α
1Release, repeat 3 times.Concrete assay method slightly.
4.ELISA method detects T α 1 blood plasma level and medication
Adopt the ELISA method to measure volunteer's blood plasma T α
1Level.At first measure preceding 6 the healthy volunteer's blood plasma T α of administration
1Level.Give T α
1Raw material medicated powder 5mg measures T α
1Level.After 1 week, give 6 healthy volunteer embodiment the T α of 10 preparations more respectively
1Microsphere 5mg measures the T α in the blood plasma
1Level.
Concrete assay method is summarized as follows: with T α
1Prepare the anti-T α of rabbit with the coupling complex immunity new zealand white rabbit of BSA
1Polyclonal antibody.With T α
1(200ng/ml) 100 μ l coated elisa plates, 4 ℃ of overnight incubation, spend the night with 4 ℃ of sealings of 3% gelatin after washing plate, remove confining liquid, every hole adds the standard substance of variable concentrations or the abundant mixing of antiserum 50 μ l of plasma specimen to be measured 50 μ l and dilution after washing plate, hatch 120min for 37 ℃, add biotin labeled goat anti-rabbit antibody diluent 100 μ l after washing plate, hatch 60min for 37 ℃, wash the horseradish peroxidase diluent 100 μ l that add the Avidin labelling behind the plate, hatch 60min for 37 ℃, wash and add the OPD colour developing behind the plate, indicate the absorbance of surveying 490nm on the instrument at enzyme.All mensuration are represented with the mean value standard deviation, relatively adopt non-paired t test between group.The blank plasma of administration is not determined at the 1st day 10:00 in the morning and carries out; 8:00 gave crude drug the 2nd day morning, and the 9th day morning, 8:00 gave enteric-coated microsphere, 1,2,5 and 8 hour blood plasma T α behind mensuration orally give crude drug and the microsphere
1Level.
Three, embodiment
Embodiment 1:
Tα
1 100mg
Phosphate buffer 1 0ml
Acrylic resin II 5.0g
Ethanol is an amount of
Gelatin solution 50ml
Prepare enteric-coated microsphere according to above basic preparation method, the microsphere of preparation is carried out the mensuration of morphologic observation and capacity antacid and enteric ability.The results are shown in Table 1.
Embodiment 2
Tα
1 100mg
Phosphate buffer 1 0ml
Phthalic acid hypromellose ester 5.0g
Ethanol is an amount of
Gelatin solution 50ml
Prepare enteric-coated microsphere according to above basic preparation method, the microsphere of preparation is carried out the mensuration of morphologic observation and capacity antacid and enteric ability.The results are shown in Table 1.
Embodiment 3
Tα
1 100mg
Phosphate buffer 1 0ml
Cellulose acetate phthalate ester 5.0g
Ethanol is an amount of
Gelatin solution 50ml
Prepare enteric-coated microsphere according to above basic preparation method, the microsphere of preparation is carried out the mensuration of morphologic observation and capacity antacid and enteric ability.The results are shown in Table 1.
Embodiment 4
Tα
1 100mg
Phosphate buffer 1 0ml
Lac 5g
Ethanol is an amount of
Gelatin solution 50ml
Prepare enteric-coated microsphere according to above basic preparation method, the microsphere of preparation is carried out the mensuration of morphologic observation and capacity antacid and enteric ability.The results are shown in Table 1.
Embodiment 5
Tα
1 100mg
Hyaluronidase 5mg
Phosphate buffer 1 0ml
Acrylic resin II 5.0g
Ethanol is an amount of
Gelatin solution 50ml
Prepare enteric-coated microsphere according to above basic preparation method, wherein hyaluronidase and T α 1 together are dissolved in phosphate buffer; The microsphere of preparation is carried out the mensuration of morphologic observation and capacity antacid and enteric ability.The results are shown in Table 1.
Embodiment 6
Tα
1 100mg
Hyaluronidase 5mg
Phosphate buffer 1 0ml
Acrylic resin II 5.0g
Brij30 2mg
Ethanol is an amount of
Gelatin solution 50ml
Preparation method is with embodiment 5, and wherein Brij30 and other compositions together are dissolved in the ethanol; The microsphere of preparation is carried out the mensuration of morphologic observation and capacity antacid and enteric ability.The results are shown in Table 1.
Embodiment 7
Tα
1 100mg
Hyaluronidase 5mg
Phosphate buffer 1 0ml
Acrylic resin II 5.0g
Brij30 2mg
Laurocapram 2mg
Ethanol is an amount of
Gelatin solution 50ml
Preparation method is with embodiment 6, and wherein laurocapram and other compositions together are dissolved in the ethanol; The microsphere of preparation is carried out the mensuration of morphologic observation and capacity antacid and enteric ability.The results are shown in Table 1.
Embodiment 8
Tα
1 100mg
Hyaluronidase 5mg
Phosphate buffer 1 0ml
Acrylic resin II 5.0g
Brij30 2mg
Sodium cholate 2mg
Ethanol is an amount of
Gelatin solution 50ml
Preparation method is with embodiment 6, and wherein sodium cholate and other compositions together are dissolved in the ethanol; The microsphere of preparation is carried out the mensuration of morphologic observation and capacity antacid and enteric ability.The results are shown in Table 1.
Embodiment 9
Tα
1 100mg
Hyaluronidase 5mg
Phosphate buffer 1 0ml
Acrylic resin II 5.0g
Brij30 2mg
Lecithin 2mg
Ethanol is an amount of
Gelatin solution 50ml
Preparation method is with embodiment 6, and wherein lecithin and other compositions together are dissolved in the ethanol; The microsphere of preparation is carried out the mensuration of morphologic observation and capacity antacid and enteric ability.The results are shown in Table 1.
Embodiment 10
Tα
1 100mg
Hyaluronidase 5mg
Phosphate buffer 1 0ml
Acrylic resin II 5.0g
Brij30 2mg
Laurocapram 2mg
Benzyl alcohol 2mg
Ethanol is an amount of
Gelatin solution 50ml
Preparation method is with embodiment 6, and wherein benzyl alcohol and other compositions together are dissolved in the ethanol; The microsphere of preparation is carried out the mensuration of morphologic observation and capacity antacid and enteric ability.The results are shown in Table 1.
Four, testing result
1. release conditions in the acidproof situation of microsphere and the simulated intestinal fluid
Table 1 T α 1 enteric-coated microsphere character is investigated the result
| Embodiment number | Morphology | Burst size (%) in acid-resistant strength (2h) acid | 1h release (%) in the simulated intestinal fluid | |
| Particle diameter (μ m) | Volumetric diameter (μ m) | |||
| Embodiment 1 embodiment 2 embodiment 3 embodiment 4 embodiment 5 embodiment 6 embodiment 7 embodiment 8 embodiment 9 embodiment 10 | 4.96 4.78 5.02 4.69 4.88 4.90 4.65 4.77 4.81 5.11 | 5.88 5.74 6.11 5.67 5.52 5.84 5.26 5.65 5.99 6.02 | 12.5, light microscopic keeps circular 14.6 down, light microscopic keeps circular 13.8 down, light microscopic keeps circular 14.2 down, light microscopic keeps circular 12.8 down, light microscopic keeps circular 12.7 down, light microscopic keeps circular 9.8 down, light microscopic keeps circular 12.1 down, light microscopic keeps circular 12.0 down, light microscopic keeps circle 10.8 down, and it is circular that light microscopic keeps down | 95.6 96.2 95.3 94.6 96.5 96.8 95.3 95.1 95.9 96.7 |
The result is as seen: the microsphere acid-resistant strength is better, discharges 1h and promptly almost all discharge in simulated intestinal fluid.
2.ELISA method detects T α
1Blood plasma level
The blood plasma T α of different time after 6 healthy volunteers of table 2 take medicine
1Level (mean value standard deviation, μ g/ml)
| Group | 0h | 1h after the administration | 2h after the administration | 5h after the administration |
| Do not take medicine | 0.82±0.35 | - | - | - |
| Give T α 1Crude drug 5mg | - | 1.22±0.43 | 1.28±0.39 | 0.89±0.32 |
| Give T α 1Enteric-coated microsphere 5mg | - | 0.87±0.33 | 0.95±0.36 | 3.98±0.37 |
By result in the table as seen, the blood plasma level of enteric-coated microsphere 1h and 2h after administration is than directly giving the low of crude drug, show that administration 2h discharges under one's belt basically with interior medicine, drug plasma level and being on close level of not taking medicine show that the interior acid resistance of body of microsphere is good; 5h and 8h enteric-coated microsphere preparation enter intestinal and discharge medicine after the administration, and the blood plasma level ratio of medicine gives crude drug person's height has significance (P＜0.01).Simultaneously, the AUC value of calculating enteric-coated microsphere with trapezoidal method be significantly higher than crude drug the AUC value (because of sampling time point less, unlisted AUC data).
Claims (9)
1 one kinds of novel location and small intestinal or colon delivery formulations---oral Thymosin alpha
1Enteric coated preparation, it comprises Thymosin alpha
1, absorption enhancer, gelatin and enteric material etc.
2. the oral Thymosin alpha of claim 1
1Enteric coated preparation, wherein absorption enhancer is selected from: Brij30, laurocapram, sodium cholate, NaGC, sodium taurocholate, NaTDC, capric acid, Capric acid sodium salt, oleyl alcohol, oleic acid, beta-schardinger dextrin-, EDTA-Na
2, HP-, carbomer, oxyethanol, sodium lauryl sulphate, Brij, tween, span, eudesmol, Mentholum, Borneolum Syntheticum, enoxolone, propylene glycol, glycerol, ethanol, mannitol, citric acid, phosphate buffer, sodium salicylate, lecithin, fabaceous lecithin, polyvidone, benzyl alcohol, linoleic acid, benzyl benzoate, ethyl oleate and carbamide, a kind of during the optional usefulness of absorption enhancer is above or several.
3. the oral Thymosin alpha of claim 1
1Enteric coated preparation, wherein the absorption enhancer optimum is that Brij30, laurocapram merge use.
4. the oral Thymosin alpha of claim 1
1Enteric coated preparation, wherein enteric material acrylic resin, phthalic acid hypromellose ester, cellulose acetate phthalate ester or Lac.
5. the described enteric material of claim 3 acrylic resin more preferably, model more preferably acrylic resin II number.
6. the oral Thymosin alpha of any requirement of claim 1～5
1Preparation, wherein Thymosin alpha
1Amount contain 1～20mg for each dosage unit.
7. the oral Thymosin alpha of claim 6
1Preparation, wherein Thymosin alpha
1Be that form with microsphere exists, can add appropriate excipients and be pressed into tablet or incapsulate.
8. the oral Thymosin alpha of claim 6
1The preparation method of enteric coated preparation is as follows:
Thymosin alpha
1Be dissolved in the phosphate buffer of 0.1mol/L, acrylic resin II number and other compositions are dissolved in the ethanol, with two kinds of solution mixings, under high-speed stirred, be scattered in the liquid paraffin again, slowly add gelatin solution, be stirred to microsphere and solidify centrifugal collecting precipitation, remove the liquid paraffin on surface, drying under reduced pressure 12h promptly.
9. the described oral Thymosin alpha of claim 1
1Enteric coated preparation, the application in treatment viral hepatitis, malignant tumor, immune deficiency disorder.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200510064708 CN1853718A (en) | 2005-04-18 | 2005-04-18 | Positioning composition for oral liquid and its preparation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200510064708 CN1853718A (en) | 2005-04-18 | 2005-04-18 | Positioning composition for oral liquid and its preparation |
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|---|---|
| CN1853718A true CN1853718A (en) | 2006-11-01 |
Family
ID=37194370
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200510064708 Pending CN1853718A (en) | 2005-04-18 | 2005-04-18 | Positioning composition for oral liquid and its preparation |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102228680A (en) * | 2011-06-14 | 2011-11-02 | 中国人民解放军第三○二医院 | Thymosin phospholipids/bile salt compound micelle and preparation method and preparation thereof |
| CN102633637A (en) * | 2012-03-30 | 2012-08-15 | 吉林大学 | Pharmaceutical formula for effectively relieving and treating constipation |
| CN107281163A (en) * | 2017-07-05 | 2017-10-24 | 郑州大学 | Application of the carboxyl compound in terms of drug-carrying nanometer particle microballoon oral absorption is promoted |
-
2005
- 2005-04-18 CN CN 200510064708 patent/CN1853718A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102228680A (en) * | 2011-06-14 | 2011-11-02 | 中国人民解放军第三○二医院 | Thymosin phospholipids/bile salt compound micelle and preparation method and preparation thereof |
| CN102228680B (en) * | 2011-06-14 | 2013-02-27 | 中国人民解放军第三0二医院 | Thymosin phospholipids/bile salt compound micelle and preparation method and preparation thereof |
| CN102633637A (en) * | 2012-03-30 | 2012-08-15 | 吉林大学 | Pharmaceutical formula for effectively relieving and treating constipation |
| CN107281163A (en) * | 2017-07-05 | 2017-10-24 | 郑州大学 | Application of the carboxyl compound in terms of drug-carrying nanometer particle microballoon oral absorption is promoted |
| CN107281163B (en) * | 2017-07-05 | 2020-08-14 | 郑州大学 | Application of carboxyl compound in aspect of promoting oral absorption of drug-loaded nanoparticle microspheres |
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