CN103495152B - Thymopentin-containing medicine composition, as well as preparation and preparation method thereof - Google Patents
Thymopentin-containing medicine composition, as well as preparation and preparation method thereof Download PDFInfo
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- CN103495152B CN103495152B CN201310469885.5A CN201310469885A CN103495152B CN 103495152 B CN103495152 B CN 103495152B CN 201310469885 A CN201310469885 A CN 201310469885A CN 103495152 B CN103495152 B CN 103495152B
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Abstract
The invention belongs to the technical field of medicines, and in particular relates to a thymopentin-containing medicine composition, as well as a preparation and a preparation method thereof. The medicine composition provided by the invention comprises thymopentin and mannitol, wherein the mass ratio of the thymopentin to the mannitol is 1:(18-25), preferably 1:(18-22), and more preferably 1:19. The preparation of the medicine composition provided by the invention is a freeze-dried powder injection. The pH value of the freeze-dried powder injection can be constantly kept within the range of 6-8 to achieve slight fluctuation and quite good stability without the need of adding a pH regulator in the prescription, and therefore the prejudice that the pH regulator needs to be added in the prescription of the thymopentin freeze-dried powder injection for injection in the prior art is overcome.
Description
Technical field
The invention belongs to medical art, specifically, relate to a kind of pharmaceutical composition, preparation and preparation method containing Thymopentin.
Background technology
Thymopentin (TP-5) is 32 to 36 amino acids sequences of the pentapeptide (Arg-Lys-Asp-Val-Tyr) of synthetic, corresponding thymopoietin, and all biological with natural thymopoietin is active.As Culture in vitro medicine, there is inducing T cell differentiation on the one hand, promote that t lymphocyte subset group reaches maturity and the function activated, macrophage phagocytic function can be strengthened again on the one hand and strengthen hematid immunity function, improve generation level and the receptor expression level of natural killer cell activity and interleukin-2, strengthen the generation of peripheral blood lymphocytes gamma interferon, strengthen superoxide dismutase activity in serum.In clinical, Thymopentin has been widely applied to the treatment of such as malignant tumor, the treatment of chronic, viral hepatitis, operating post-operative recovery, in multiple fields such as the treatment of elderly and infirm's immunologic hypofunction, and Be very effective.
Thymopentin is made up of Arg-Lys-Asp-Val-Tyr, the peptide bond less stable of Asp in its strand, easy fracture in aqueous solution or acid solution, be degraded to corresponding dipeptides (Val-Tyr) and tripeptides (g-Lys-Asp), affect product quality, being prepared into water-free lyophilized injectable powder is one of method solving this problem.
The Thymopentin injection gone on the market is lyophilization injectable powder, as Li Er peptide (thymopentin for injection (tp-5)), Main Ingredients and Appearance is Thymopentin, adjuvant is mannitol, sodium dihydrogen phosphate, sodium hydrogen phosphate, wherein sodium dihydrogen phosphate and sodium hydrogen phosphate are pH adjusting agent, adjust ph reaches suitable stable equilibrium, thus plays Stabilization.
" technical study of thymopentin for injection (tp-5) " [Liu Lian, Dong Shuchun. the technical study of thymopentin for injection (tp-5), the science and technology world] report a kind of prescription and technique of thymopentin for injection (tp-5), wherein prescription is: Thymopentin 1g, mannitol 5g, sodium phosphate buffer adjust pH 6.0-8.0, water for injection, to 100ml, makes 100.Technique is: take the Thymopentin of recipe quantity, mannitol joins in the water for injection of full dose 80%, abundant stirring makes it dissolve, water for injection standardize solution is to full dose, with sodium phosphate buffer adjust pH at 6.0-8.0, the active carbon adding 0.1% stirs placement 15 minutes, decarburization, with the filtering with microporous membrane of 0.22 μm; Fill; Jump a queue; Lyophilization; Gland; Visual inspection.
Master thesis " experimentatioies of two kinds of Thymopentin preparations " reports a kind of thymopentin for injection (tp-5) and technique, wherein prescription is: Thymopentin 1.0g, mannitol 50g, 0.1mol hydrochloric acid solution adjust pH6.5-7.8 and water for injection to 1000ml, make 1000 bottles.
CN101411864A discloses a kind of thymopentin dry powder formulation and preparation method thereof.The method, is that excipient is soluble in water, obtains solution I, filtering solution I, collects filtrate I; Thymopentin is added in filtrate I, obtain solution II, filtering solution II, collect filtrate II; Then described filtrate II is carried out lyophilization, obtain thymopentin dry powder formulation; Described excipient is any one in mannitol, lactose and glycine.Wherein, phosphate solution is adopted to regulate the pH value of evaluation of thymopentin in solution and pH value is adjusted to 7.0-7.3 in the method.
CN102138908A discloses a kind of Thymopentin lyophilization powder injection for injection agent and preparation technology thereof.The method is: joined by mannitol in water for injection, be stirred to dissolve, then add Thymopentin, and stirring makes entirely molten.Controlling medicinal liquid pH value is 6.8, mends and injects water to 1000ml.Use 0.2% active carbon, absorption, decarburization are filtered, and filtrate is filtered, and gained clear solution subpackage, lyophilization are obtained Thymopentin lyophilization powder injection for injection agent.
CN102988954A discloses a kind of freeze-dried pharmaceutical formulation containing Thymopentin, is made up of the component of following proportioning: Thymopentin 0.5-2g, mannitol 100-200g, EDTA calcium 1-3g, vitamin C 1-2g, mol ratio are that the DisodiumHydrogen Citrate of 1:4 and trisodium citrate buffer 1000ml and water for injection are settled to 2000ml.In this freeze-dried pharmaceutical formulation, adopt DisodiumHydrogen Citrate and trisodium citrate buffer to make the pH value of solution remain on 6.9-7.1, ensure its stability.
Visible, in prior art, in order to make the pH value of evaluation of thymopentin in solution more stable, thus make Thymopentin more stable in the solution, therefore, in the preparation process of Thymopentin lyophilization powder injection for injection agent, all with the addition of a certain amount of pH adjusting agent to ensure its stability.PH adjusting agent used adopts the reagent such as hydrochloric acid, sodium hydroxide, phosphate or sodium bicarbonate usually, fact proved, adopt as above after pH adjusting agent adjust ph, the stability of Thymopentin is also bad, and in use for avoiding medicine variable color still to need low temperature storage.
In the Thymopentin pharmaceutical composition of prior art, for ensureing the stability of Thymopentin, all contain other pharmaceutic adjuvant except mannitol, but the increase of pharmaceutic adjuvant kind certainly will increase potential drug risk.The present invention by a large amount of tests, the constantly ratio of adjustment Thymopentin and mannitol, surprisingly the solution of discovery Thymopentin when the mass ratio of Thymopentin and mannitol is 1:18 ~ 25 has good stability, and pH value fluctuates very little in 6 ~ 8 scopes; And mass ratio when being 1:18 ~ 22 stability better, when mass ratio is 1:19, its stability reaches best.
The present invention also provides a kind of preparation, and described preparation contains pharmaceutical composition of the present invention.
In the present invention, described preparation is lyophilized injectable powder.
The Thymopentin lyophilization powder injection for injection agent of prior art, in order to make the pH value of evaluation of thymopentin in solution more stable, thus makes Thymopentin more stable in the solution, in its preparation process, all with the addition of a certain amount of pH adjusting agent to ensure its stability.The present inventor is through large quantifier elimination, a kind of pharmaceutical composition with better stability is obtained by the mass ratio of adjustment Thymopentin and mannitol, and no longer need to add its pH value of pH adjusting agent when adopting this pharmaceutical composition to be prepared into lyophilized injectable powder in its prescription just can be constant in 6 ~ 8 scopes, fluctuate very little, and there is good stability, thus overcome in the prescription of Thymopentin lyophilization powder injection for injection agent in prior art the prejudice needing to add pH adjusting agent.
Lyophilized injectable powder of the present invention can be prepared into pharmaceutically common specification, and as in Thymopentin, 10mg/ props up or 1mg/ props up, and as a kind of preferred version, the specification of lyophilized injectable powder of the present invention is counted 1mg/ with Thymopentin and propped up.
Specifically, lyophilized injectable powder of the present invention makes 1000 by following component through lyophilization:
Thymopentin 1g
Mannitol 18 ~ 25g
Water for injection adds to 1000ml;
Preferably make 1000 by following component through lyophilization:
Thymopentin 1g
Mannitol 18 ~ 22g
Water for injection adds to 1000ml;
More preferably 1000 are made by following component through lyophilization:
Thymopentin 1g
Mannitol 19g
Water for injection adds to 1000ml.
Show through accelerated test and long-term stable experiment, comparatively prior art is compared with commercial samples, and the Thymopentin lyophilized injectable powder obtained by the present invention has good stability equally when not using pH adjusting agent.
In the present invention, described Thymopentin can be commercially available Thymopentin crude drug, as the Thymopentin crude drug that Shanghai Zineng Pharmaceutical Co., Ltd. provides, the synthetic method of prior art also can be adopted to synthesize and obtain.But as one of the present invention most preferably scheme, Thymopentin of the present invention is Thymopentin hydrate crystal, the molecular formula of described Thymopentin hydrate crystal is C
30h
49n
9o
93.5H
2the X-ray powder diffractogram that the measurement of O, use Cu-K alpha ray obtains as shown in Figure 1.
In the present invention, described Thymopentin hydrate crystal is adopted and is prepared with the following method:
At ambient temperature, Thymopentin is dissolved in distilled water, cross and filter insoluble matter, then in gained solution, add the mixed solution of isopropyl alcohol and ether, leave standstill 5 ~ 6 hours at 0 ~ 5 DEG C, obtain white crystal, filter, filter cake washing with alcohol, vacuum drying 2 ~ 4 hours, obtains Thymopentin hydrate crystal.
Wherein, described Thymopentin and the mass ratio of distilled water are 1:2 ~ 1:4.
In described mixed solution, the volume ratio of isopropyl alcohol and ether is 1:2 ~ 1:3.5.
Described distilled water and the volume ratio of mixed solution are 1:8 ~ 1:12.
Material due to by the impact of various factors, makes in molecule or molecular linkage mode changes when crystallization, cause molecule or atom different in lattice vacancy arrangement, form different crystal structures.Polymorph in pharmaceuticals phenomenon is one of key factor affecting drug quality and clinical efficacy, and therefore in Control of drug quality, crystal formation is one of them important quality control index.The polymorphism of medicine has important impact to the quality of product such as stability etc.Thymopentin raw material has the character of case of thermal instability.Whether can by changing crystallization condition and make in Thymopentin molecule or molecular linkage mode changing, cause molecule or atom different in lattice vacancy arrangement, thus form a kind of different Thymopentin crystal structure.For this reason, the present inventor is after having carried out large quantifier elimination to Thymopentin, a kind of Thymopentin hydrate crystal with novel crystal forms structure is obtained by changing crystallization condition, find through test, the Thymopentin of this novel crystal forms structure has good stability to heat, and the Thymopentin lyophilized injectable powder adopting the Thymopentin hydrate crystal of this novel crystal forms structure to obtain has more excellent stability.
The present invention also provides the preparation method of described preparation further, and described preparation method comprises the steps:
1) take Thymopentin and mannitol by described consumption, add appropriate water for injection and dissolve, obtain medicinal liquid;
2) in the medicinal liquid of step 1) gained, add active carbon, stir, leave standstill, by microporous filter membrane decarburization, obtain decarbonizing liquid;
3) measure above-mentioned medicinal liquid content, add to the full amount of water for injection, through microporous filter membrane fine straining, obtain fine straining liquid;
4) by gained fine straining liquid subpackage, half tamponade, lyophilization, roll lid, packaging, obtain described lyophilized injectable powder.
At present, when preparing Thymopentin lyophilization powder injection for injection agent, in the adsorption process of active carbon, with activated carbon adsorption Thymopentin and mannitol rare join solution usually, or join solution with the rare of activated carbon adsorption mannitol.In the present invention, by the investigation to active carbon absorption technology, surprisingly discovery activated carbon adsorption Thymopentin and the dense of mannitol join solution, and the content of obtained freeze-drying injectable powder is apparently higher than the rare lyophilized injectable powder of joining solution gained with activated carbon adsorption Thymopentin and mannitol.
In the present invention, described rare solution of joining is be settled to the solution after full dose with water for injection, and described dense solution of joining is solution after dissolving with appropriate water for injection.
In addition, prior art, when preparing Thymopentin lyophilization powder injection for injection agent, all with the addition of a certain amount of pH adjusting agent to ensure Thymopentin stability in the solution.The present invention is by the adjustment of mass ratio of Thymopentin and mannitol, the improvement of preparation technology, as the adjustment of activated carbon adsorption solution, be surprised to find that Thymopentin lyophilized injectable powder of the present invention does not need to add pH adjusting agent in the preparation and just can ensure Thymopentin stability in the solution.
In preparation method of the present invention, wherein, the lyophilization described in step 4) is divided into pre-freeze, distillation and dry three periods, wherein pre-freeze phase: set condenser temperature as-45 DEG C, put into goods, products temperature is down to-45 DEG C, keep 6 ~ 7 hours; The distillation phase: it is 13.33Pa that condenser is evacuated to vacuum, and products temperature is warming up to-20 DEG C with 0.5 ~ 1 DEG C/h; Dry period: continue, under vacuum 13.33Pa, products temperature to be warming up to 0 DEG C with 2 DEG C/h, then be warming up to 15 DEG C with 3 DEG C/h.
Freeze drying process directly affects the mouldability of freeze-drying prods, mechanical strength and water content etc., only has and selects suitable freeze drying process just can produce all qualified product of indices.Lyophilization of the present invention comprises pre-freeze, distillation and dry 3 stages.The first step of freezing dry process is pre-freeze, after fill terminates and after loading condenser, by medicinal liquid fully charge, make it progressively to reach final solidification point, in this process, solute is crystallization gradually, the crystal of ice is grown up gradually, and large owing to freezing ice crystal in body, the gap between solute nucleus and ice is larger, be conducive to the eliminating of subliming water, shorten drying time.
After medicinal liquid fully charge, reduce the pressure in hothouse by the method for evacuation, when making it the saturated vapor pressure lower than steam at this temperature, ice distils, and moisture is constantly pumped, and product is constantly dry.This is sublimation stage.In this stage, if from-45 DEG C ~-20 DEG C these intensification sections, do not control its programming rate, but rise to-20 DEG C fast from-45 DEG C, like this because goods programming rate is too fast, condenser has little time the moisture of distillation all to trap, thus causes chemical medicine or freeze type bad.Programming rate controls at 0.5 ~ 1 DEG C/h by the present invention, makes programming rate relatively steady, goods can be made like this to distil under more balanced condition.
In sublimation process, most moisture is progressively got rid of along with the distillation of ice crystal.If under the goods of sublimation drying are placed in room temperature, moisture residual in goods is enough to goods to decompose.In order to reach good drying regime, should drying be carried out, its objective is and remove moisture residual in goods further.This is drying stage.Extend drying time and can reduce moisture, but the unconfined prolongation redrying time, the cost of medicine will be strengthened.In the present invention, after being warming up to-20 DEG C, first programming rate being brought up to 2 DEG C/h and be warming up to 0 DEG C, then be warming up to 15 DEG C with 3 DEG C/h, it is more satisfactory that the finished product of gained freezes type, and be loose block, shape is full, not atrophy, adds water instant.
In preparation method of the present invention, step 2) described in the consumption of active carbon be 0.1%w/v, described stirring is stirring 10 minutes.
In preparation method of the present invention, step 2) described in microporous filter membrane be 0.8 μm of microporous filter membrane; Microporous filter membrane described in step 3) is 0.22 μm of microporous filter membrane.
Compared with prior art, tool of the present invention has the following advantages:
(1) pharmaceutical composition containing Thymopentin provided by the present invention is only containing active component Thymopentin and a small amount of pharmaceutic adjuvant mannitol, thus decreases because of supplementary product kind and the many and potential drug risk that brings of consumption;
(2) pharmaceutical composition containing Thymopentin provided by the present invention has good stability;
(3) preparation of the pharmaceutical composition containing Thymopentin provided by the present invention is lyophilized injectable powder, not needing to add its pH value of pH adjusting agent in its prescription just can be constant in 6 ~ 8 scopes, fluctuate very little, and there is good stability, thus overcome in the prescription of Thymopentin lyophilization powder injection for injection agent in prior art the prejudice needing to add pH adjusting agent;
(4) preparation method of lyophilized injectable powder provided by the present invention is by the adjustment of mass ratio of Thymopentin and mannitol, the improvement of preparation technology, as the adjustment of activated carbon adsorption solution, the design of lyophilization curve, is surprised to find that Thymopentin lyophilized injectable powder of the present invention does not need to add pH adjusting agent in the preparation and just can ensure Thymopentin stability in the solution;
(5) present invention also offers a kind of Thymopentin hydrate crystal, because this hydrate crystal has good stability to temperature, thus the Thymopentin lyophilized injectable powder adopting this hydrate crystal to obtain has more excellent stability.
Summary of the invention
For overcoming above-mentioned defect, object of the present invention is just to provide a kind of pharmaceutical composition and the preparation thereof that contain Thymopentin, and described preparation is lyophilized injectable powder, and this lyophilized injectable powder does not need to add any pH adjusting agent just can have good stability.
For realizing object of the present invention, the present invention adopts following technical scheme:
A pharmaceutical composition containing Thymopentin, wherein, described pharmaceutical composition is made up of Thymopentin and mannitol, and wherein the mass ratio of Thymopentin and mannitol is 1:18 ~ 25, preferred 1:18 ~ 22, more preferably 1:19.
Accompanying drawing explanation
Fig. 1 is the X-ray powder diffraction spectrogram of Thymopentin hydrate crystal of the present invention;
Fig. 2 is the TG figure of Thymopentin hydrate crystal of the present invention;
Fig. 3 is the DSC figure of Thymopentin hydrate crystal of the present invention.
Detailed description of the invention
Be below the specific embodiment of the present invention, described embodiment is to describe the present invention, instead of restriction the present invention.
Embodiment 1
A pharmaceutical composition containing Thymopentin, is made up of Thymopentin 1 weight portion and mannitol 19 weight portion.
The preparation of this pharmaceutical composition is lyophilized injectable powder, its prescription and preparation method as follows:
Prescription:
Preparation method:
1) take Thymopentin and mannitol by described consumption, add 100ml water for injection and dissolve, obtain medicinal liquid;
2) in the medicinal liquid of step 1) gained by 0.1%(w/v) amount add active carbon 0.1g, stir 10 minutes, leave standstill, by 0.8 μm of microporous filter membrane decarburization, obtain decarbonizing liquid;
3) measure above-mentioned medicinal liquid content, add to the full amount of water for injection, namely contain Thymopentin 1mg to every ml, through 0.22 μm of microporous filter membrane fine straining, obtain fine straining liquid;
4) gained fine straining liquid carried out subpackage, half tamponade, lyophilization by every bottle of 1ml, roll lid, pack, obtain described thymopentin for injection (tp-5); Wherein, the lyophilization described in step 4) is divided into pre-freeze, distillation and dry three periods, wherein pre-freeze phase: set condenser temperature as-45 DEG C, put into goods, products temperature is down to-45 DEG C, keep 6 ~ 7 hours; The distillation phase: condenser freezes, and being evacuated to vacuum is 13.33Pa, and products temperature is warming up to-20 DEG C with 0.5 ~ 1 DEG C/h; Dry period: continue, under vacuum 13.33Pa, products temperature to be warming up to 0 DEG C with 2 DEG C/h, then be warming up to 15 DEG C with 3 DEG C/h.
Embodiment 2
A pharmaceutical composition containing Thymopentin, is made up of Thymopentin 1 weight portion and mannitol 18 weight portion.
The preparation of this pharmaceutical composition is lyophilized injectable powder, its prescription and preparation method as follows:
Prescription:
Preparation method: with embodiment 1.
Embodiment 3
A pharmaceutical composition containing Thymopentin, is made up of Thymopentin 1 weight portion and mannitol 25 weight portion.
The preparation of this pharmaceutical composition is lyophilized injectable powder, its prescription and preparation method as follows:
Prescription:
Preparation method: with embodiment 1.
Embodiment 4
A pharmaceutical composition containing Thymopentin, is made up of Thymopentin 1 weight portion and mannitol 22 weight portion.
The preparation of this pharmaceutical composition is lyophilized injectable powder, its prescription and preparation method as follows:
Prescription:
Preparation method: with embodiment 1.
Embodiment 5
The preparation of Thymopentin hydrate crystal:
At ambient temperature, 26g Thymopentin is dissolved in 52ml distilled water, cross and filter insoluble matter, then in gained solution, add the mixed solution (wherein the volume ratio of isopropyl alcohol and ether is 1:2) of 416ml isopropyl alcohol and ether, leave standstill 6 hours at 0 DEG C, obtain white crystal, filter, filter cake washing with alcohol twice, vacuum drying 2 hours, obtains the Thymopentin hydrate crystal of 3.5 water of crystallization.
The X-ray powder diffractogram measurement of the Thymopentin hydrate crystal of gained use Cu-K alpha ray obtained as shown in Figure 1, thermogravimetric analysis shows (as Fig. 2, Fig. 3), containing the moisture content of 8.45% in this Thymopentin hydrate crystal, this and the result containing 3.5 water of crystallization (theoretical value is 8.48%), within range of error, have an absworption peak at 194.1 DEG C.
Embodiment 6
The preparation of Thymopentin hydrate crystal:
At ambient temperature, 26g Thymopentin is dissolved in 104ml distilled water, cross and filter insoluble matter, then in gained solution, add the mixed solution (wherein the volume ratio of isopropyl alcohol and ether is 1:3.5) of 1040ml isopropyl alcohol and ether, leave standstill 5 hours at 5 DEG C, obtain white crystal, filter, filter cake washing with alcohol twice, vacuum drying 4 hours, obtains the Thymopentin hydrate crystal of 3.5 water of crystallization.
The measurement of Cu-K alpha ray and thermogravimetric analysis is used by the Thymopentin hydrate crystal of gained to show, consistent with embodiment 5.
Embodiment 7
The preparation of Thymopentin hydrate crystal:
At ambient temperature, 26g Thymopentin is dissolved in 78ml distilled water, cross and filter insoluble matter, then in gained solution, add the mixed solution (wherein the volume ratio of isopropyl alcohol and ether is 1:2.5) of 936ml isopropyl alcohol and ether, leave standstill 5.5 hours at 3 DEG C, obtain white crystal, filter, filter cake washing with alcohol twice, vacuum drying 3 hours, obtains the Thymopentin hydrate crystal of 3.5 water of crystallization.
The measurement of Cu-K alpha ray and thermogravimetric analysis is used by the Thymopentin hydrate crystal of gained to show, consistent with embodiment 5.
Embodiment 8
Pharmaceutical composition containing Thymopentin and a lyophilized injectable powder thereof, its composition and preparation method are with embodiment 1, and Thymopentin used is as different from Example 1 the Thymopentin hydrate crystal that embodiment 5 obtains.
Embodiment 9
Pharmaceutical composition containing Thymopentin and a lyophilized injectable powder thereof, its composition and preparation method are with embodiment 1, and Thymopentin used is as different from Example 2 the Thymopentin hydrate crystal that embodiment 6 obtains.
Embodiment 10
Pharmaceutical composition containing Thymopentin and a lyophilized injectable powder thereof, its composition and preparation method are with embodiment 1, and Thymopentin used is as different from Example 3 the Thymopentin hydrate crystal that embodiment 7 obtains.
Test example 1
1, prescription and technological design
The present invention has carried out trial-manufacture of sample with mannitol, lactose, Dextran 40 for filler respectively.In table 1.
Table 1, thymopentin for injection (tp-5) prescription screening form
Basic technology: Thymopentin and filler are dissolved with 100ml water for injection, add 0.1g active carbon, stir 10 minutes, medicinal liquid is by 0.8 μm of microporous filter membrane decarburization, then through 0.22 μm of microporous filter membrane fine straining, subpackage, 1ml/ props up, lyophilizing.
2, prescription screening result
Investigate the outward appearance of preparation, acid-base value, the clarity of solution and color, related substance and content results respectively in table 2.
Table 2, thymopentin for injection (tp-5) prescription screening result
Conclusion: the trial-production simultaneously having carried out three prescriptions, result prescription 1 is more excellent, therefore selects prescription 1 as the prescription of research further.
3, mannitol consumption screening
Take Thymopentin and mannitol by following dosage, by above-mentioned process trial sample, measure acid-base value, total related substance and content, the quality filtering out suitable Thymopentin and mannitol compares scope.Result is as follows:
Table 3, mannitol consumption the selection result
| Prescription is numbered | 4 | 5 | 6 | 7 | 8 | 9 | 10 | 11 | 12 |
| Thymopentin (mg) | 100 | 100 | 100 | 100 | 100 | 100 | 100 | 100 | 100 |
| Mannitol (mg) | 1700 | 1750 | 1800 | 1900 | 2000 | 2200 | 2400 | 2500 | 2550 |
| Acid-base value | 5.93 | 5.92 | 6.95 | 6.97 | 6.99 | 6.98 | 7.12 | 7.15 | 8.38 |
| Total related substance (%) | 0.61 | 0.58 | 0.18 | 0.16 | 0.19 | 0.19 | 0.28 | 0.29 | 0.59 |
| Content (%) | 97.31 | 97.35 | 99.36 | 99.38 | 99.41 | 99.63 | 99.59 | 99.51 | 98.17 |
As can be seen from above-mentioned the selection result, when the mass ratio of Thymopentin and mannitol is 1:18 ~ 25, the pH value of evaluation of thymopentin in solution fluctuates very little in 6 ~ 8 scopes, and total related substance is lower than 0.30%; And mass ratio when being 1:18 ~ 22 total related substance lower than 0.20%; Further, when mass ratio is 1:19, total its related substances is minimum.Therefore, determine that the mass ratio 1:19 of Thymopentin and mannitol is most preferably prescription of the present invention.
4, Study on Preparation
Prescription screening result shows, obviously reduces by the sample size of above-mentioned process trial, is caused by activated carbon adsorption, therefore, increases that a step is dense joins in process, dense join after with activated carbon adsorption, decarburization, rarely joins, and result content is without significant change.
Results contrast is in table 4.
Table 4, thymopentin for injection (tp-5) process optimization content results
Conclusion: dense charcoal absorbing process of joining obviously is better than rarely joining charcoal absorbing process, therefore selects densely to join charcoal absorbing process.
5, freeze drying process research
Freeze drying process directly affects the mouldability of freeze-drying prods, mechanical strength and water content etc., only has and selects suitable freeze drying process just can produce all qualified product of indices.The present invention designs 3 freeze drying process pilot sample respectively, investigates the indices of sample, filters out best freeze-dry process by comparing.
The comparison of table 5, freeze drying process
Investigate the indices of 3 kinds of freeze drying process gained samples, interpretation of result is in table 6.
The comparison of table 6, lyophilizing sample
| Sample 1 | Sample 2 | Sample 3 | |
| Mouldability | Generally | Better | Good |
| Mechanical strength | Generally | Better | Good |
| Dissolubility | Better | Better | Better |
| Water content | 5.09% | 5.27% | 3.18% |
| Content | 99.27% | 99.49% | 99.98% |
As can be seen from Table 6, the mouldability of the sample of freeze drying process 3 gained and mechanical strength all comparatively the first two technique are good, and dissolubility and content 3 kinds of samples are more or less the same, and the sample of water content technique 3 gained is minimum.Consider, the present invention selects freeze drying process 3 as the freeze-dry process of this product.
6, factors influencing
By the most preferably prescription determined and technique, prepare a batch sample, according to the method in Chinese Pharmacopoeia version stability of drug products test direction principle in 2000, sample thief respectively, exposure was placed on high temperature (60 ± 2 DEG C), lower 10 days of high humidity (relative humidity 92.5%), illumination (4500 ± 500lx) condition, respectively at sampling in 0,5,10 day, investigate, the results are shown in Table 7, table 8 and table 9.
6.1, hot test
Sample thief, exposes and to be placed in 60 DEG C of baking ovens 10 days, the results are shown in Table 7.
Table 7, thymopentin for injection (tp-5) high temperature (60 DEG C) result of the test
Result shows: high temperature 60 DEG C 10 days, and indices has no significant change, and prompting this product is to high-temperature stable.
6.2, high wet test
Sample thief, exposure is placed on and is placed with KNO
3in the exsiccator of saturated solution 10 days, investigate and the results are shown in Table 8.
Table 8, thymopentin for injection (tp-5) high humidity (RH92.5%) result of the test
Result shows: high humidity (RH92.5%) 10 days, Thymopentin related substance slightly increases.
6.3, exposure experiments to light
Sample thief, exposes and is placed in illumination meter, and adjustment illumination, at 4500 ± 500lx, 10 days, is investigated and be the results are shown in Table 9.
Table 9, thymopentin for injection (tp-5) illumination (4500 ± 500lx) result of the test
Result shows: illumination (4500 ± 500lx) 10 days, Thymopentin related substance slightly increases.
7, sample amplification technique is investigated
By the most preferably prescription determined and technique, carried out the trial-production of each 1000 bottles of three batch samples, lot number is respectively: 111201,111202,111203, and yield is respectively: 88.1%, 88.9%, 88.8%, and every quality index all conforms with the regulations.The results are shown in Table 10.
Table 10, three batches of thymopentin for injection (tp-5) amplify sample quality testing result (%)
Note: Thymopentin used in this test example is commercially available crude drug.
Show prescription of the present invention and feasible process.
Test example 2
This test example has investigated the stability of different Thymopentin to temperature.
Sample number into spectrum is as follows:
Test specimen 1: the Thymopentin hydrate crystal that the embodiment of the present invention 5 is obtained;
Test specimen 2: the Thymopentin hydrate crystal that the embodiment of the present invention 6 is obtained;
Control sample: commercially available Thymopentin crude drug, Shanghai Zineng Pharmaceutical Co., Ltd. provides;
Condition: 60 DEG C of glass are airtight, two weeks.
Changes of contents result is as following table 11:
Table 11, different Thymopentin are to the stability of temperature
| Before placement (%) | After two weeks (%) | Content declines (%) | |
| Test specimen 1 | 99.7 | 99.5 | 0.2 |
| Test specimen 2 | 99.8 | 99.5 | 0.3 |
| Control sample | 99.3 | 97.1 | 2.2 |
Note: content assaying method: HPLC
Shown by above-mentioned result of the test, the more commercially available Thymopentin crude drug of Thymopentin hydrate crystal of the present invention compares temperature and has good stability.
Also carried out above-mentioned test to the Thymopentin hydrate crystal obtained by other embodiment of the present invention, its result obtained is similar.
Test example 3
With reference to the related request about injection in China's coastal port two annex drug substance stable test direction principles, accelerated test and long-term stable experiment are carried out to the thymopentin for injection (tp-5) of the present invention and prior art.
Sample number into spectrum is as follows:
Sample 1: the Thymopentin lyophilized injectable powder obtained according to prescription and the preparation method of the embodiment of the present invention 1;
Sample 2: the Thymopentin lyophilized injectable powder obtained according to prescription and the preparation method of the embodiment of the present invention 8;
Sample 3: the thymopentin for injection (tp-5) obtained according to prescription and the technique of thymopentin for injection (tp-5) in master thesis " experimentatioies of two kinds of Thymopentin preparations ";
Sample 4: commercially available thymopentin for injection (tp-5), trade name: fixed for ripple.
1, accelerated test
Method: by above-mentioned sample under commercially available back condition, be positioned over 40 DEG C, in the medicine stability test case of RH75%, in 0,1,2,3, June tests by study on the stability project and test method respectively, investigates character, pH value, visible foreign matters, related substance and content.And compare with 0 month result.The results are shown in Table 12.
Table 12, four kinds of sample accelerated test (40 DEG C, RH75%) results
Conclusion: four kinds of samples are under commercially available back condition, carry out accelerating the investigation that (40 DEG C, RH75%) tests 6 months, result shows, comparatively prior art is compared with commercial samples, Thymopentin lyophilized injectable powder obtained by the present invention has good stability equally when not using pH adjusting agent, and when prescription is identical with preparation method, the Thymopentin lyophilized injectable powder adopting Thymopentin hydrate crystal provided by the present invention to obtain has more excellent stability.
2, long term test
Method: by above-mentioned sample under commercially available back condition, is positioned over stability test case (25 DEG C), in 0,3, June tests by study on the stability project and test method respectively, investigates character, pH value, visible foreign matters, related substance and content.And with within 0 month, investigate result and compare.The results are shown in Table 13.
Table 13, four kinds of sample long term test (25 DEG C) results
Conclusion: four kinds of sample commercially available backs, 6 months are investigated through long term test, result shows, comparatively prior art is compared with commercial samples, Thymopentin lyophilized injectable powder obtained by the present invention has good stability equally when not using pH adjusting agent, and when prescription is identical with preparation method, the Thymopentin lyophilized injectable powder adopting Thymopentin hydrate crystal provided by the present invention to obtain has more excellent stability.
Also carried out above-mentioned test to the Thymopentin lyophilized injectable powder obtained by other embodiment of the present invention, its result obtained is similar.
Claims (11)
1. the pharmaceutical composition containing Thymopentin, it is characterized in that, described pharmaceutical composition is made up of Thymopentin and mannitol, wherein the mass ratio of Thymopentin and mannitol is 1:18 ~ 25, described pharmaceutical composition is lyophilized injectable powder, described Thymopentin is Thymopentin hydrate crystal, and its molecular formula is C
30h
49n
9o
93.5H
2o, the X-ray powder diffractogram that described Thymopentin hydrate crystal uses the measurement of Cu-K alpha ray to obtain as shown in Figure 1.
2. pharmaceutical composition according to claim 1, is characterized in that, described Thymopentin and the mass ratio of mannitol are 1:18 ~ 22.
3. pharmaceutical composition according to claim 2, is characterized in that, the mass ratio of Thymopentin and mannitol is 1:19.
4. the pharmaceutical composition according to claim 1-3 any one, is characterized in that, described lyophilized injectable powder is made up through lyophilization of Thymopentin, mannitol and water for injection.
5. pharmaceutical composition according to claim 4, is characterized in that, the specification of described lyophilized injectable powder is counted 1mg/ with Thymopentin and propped up.
6. pharmaceutical composition according to claim 5, is characterized in that, described lyophilized injectable powder makes 1000 by following component through lyophilization:
Thymopentin 1g
Mannitol 18 ~ 25g
Water for injection adds to 1000ml.
7. pharmaceutical composition according to claim 6, is characterized in that, described lyophilized injectable powder makes 1000 by following component through lyophilization:
Thymopentin 1g
Mannitol 18 ~ 22g
Water for injection adds to 1000ml.
8. pharmaceutical composition according to claim 7, is characterized in that, described lyophilized injectable powder makes 1000 by following component through lyophilization:
Thymopentin 1g
Mannitol 19g
Water for injection adds to 1000ml.
9. a preparation method for the pharmaceutical composition described in claim 1-8 any one, is characterized in that, described preparation method comprises the steps:
1) take Thymopentin and mannitol by described consumption, add appropriate water for injection and dissolve, obtain medicinal liquid;
2) to step 1) add active carbon in the medicinal liquid of gained, stir, leave standstill, by microporous filter membrane decarburization, obtain decarbonizing liquid;
3) measure above-mentioned medicinal liquid content, add to the full amount of water for injection, through microporous filter membrane fine straining, obtain fine straining liquid;
4) by gained fine straining liquid subpackage, half tamponade, lyophilization, roll lid, packaging, obtain described lyophilized injectable powder.
10. preparation method according to claim 9, is characterized in that, step 4) described in lyophilization be divided into pre-freeze, distillation and dry three periods, the wherein pre-freeze phase: set condenser temperature as-45 DEG C, put into goods, products temperature is down to-45 DEG C, keep 6 ~ 7 hours; The distillation phase: it is 13.33Pa that condenser is evacuated to vacuum, and products temperature is warming up to-20 DEG C with 0.5 ~ 1 DEG C/h; Dry period: continue, under vacuum 13.33Pa, products temperature to be warming up to 0 DEG C with 2 DEG C/h, then be warming up to 15 DEG C with 3 DEG C/h.
11. preparation methoies according to claim 9 or 10, is characterized in that, step 2) described in the consumption of active carbon be 0.1%w/v, described stirring is stirring 10 minutes, and described microporous filter membrane is 0.8 μm of microporous filter membrane; Step 3) described in microporous filter membrane be 0.22 μm of microporous filter membrane.
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