CN103536623B - Potassium magnesium aspartate composition freeze-dried powder for injection - Google Patents

Abstract

The invention provides a potassium magnesium aspartate composition freeze-dried powder for injection, and belongs to the field of medicine and medicine preparation technology. The potassium magnesium aspartate composition freeze-dried powder comprises following raw material ingredients, by weight, 850 to 1700 parts of potassium magnesium aspartate, 164 to 328 parts of potassium hydroxide, 70 to 140 parts of magnesium oxide, 500 to 1000 parts of chitosan nanoparticle, and 4000 to 8000 parts of injection water. Advantages of the potassium magnesium aspartate composition freeze-dried powder are that: the potassium magnesium aspartate composition is made into freeze-dried powder for convenience in clinical application; the potassium magnesium aspartate composition is capable of prolonging medicine half-life period significantly, prolonging medicine action time, increasing medicine bioavailability, and reducing medicine use numbers of patient; the potassium magnesium aspartate composition freeze-dried powder injection is stable in properties, is convenient for carrying and transporting, and is capable of reducing dosage of the auxiliary materials, improving solubility of the main medicine ingredient, and ensuring clinical medication safety.

Description

Potassium magnesium aspartate for injection composite freeze-dried powder

Technical field:

The present invention relates to medicine and medicine manufacture technology field, particularly relate to a kind of potassium magnesium aspartate for injection composite freeze-dried powder.

Background technology:

Aspartic Acid is the precursor of oxaloacetic acid in body, plays an important role in tricarboxylic acid cycle.Meanwhile, Aspartic Acid also participates in ornithine cycle, promotes the metabolism of ammonia and carbon dioxide, makes it to generate carbamide, reduces the content of ammonia and carbon dioxide in blood.Aspartic Acid is comparatively strong to cellular affinity, after it is combined with potassium ion, magnesium ion, forms firm potassium salt, magnesium salt, thus the carrier making Aspartic Acid become potassium magnesium ion makes in this this two kinds of ion ingress engine somatic cell.Motassium magnessium aspartate participates in ornithine cycle, makes NH3 and CO2 generate carbamide and reaches Detoxication; It has following important physiological function: participate in tricarboxylic acid cycle, promotes energy metabolism, is the catalyst that the synthesis of high-energy phosphate compound is decomposed; Participation nucleotide generates, and is the important substance of cytothesis and regeneration; The excretion of bile and bile pigments can be promoted, have the effects such as row is yellow, minimizing liver fat, increase hepatic glycogen; Promote that T lymphocyte development is divided into mature T lymphocyte, have antiviral and antineoplastic action.

At present, potassium magnesium aspartate for injection freeze-dried powder on domestic market exists that amount of excipient is large, supplementary product kind is many, production cost is high, lyophilization cycle is long, the shortcomings such as dissolubility and solubility difference, these shortcomings bring very large limitation to clinical practice, Given this, the present invention adopts novel adjuvant---and chitosan and motassium magnessium aspartate form compositions, make lyophilized injectable powder, greatly reduce the consumption of excipient, simple process, production cost are low, lyophilizing finished product redissolves effective, fundamentally solves the problems referred to above.The adjuvant chitosan that the present invention adopts is a kind of natural polymers, belong to aminopolysaccharide, it is the alkaline polysaccharide of unique band cationic property found up to now, chitosan is widespread in nature in unicellular lower eukaryote mushroom, the cell of algae, the shell etc. of a joint animal shrimp, Eriocheir sinensis, insecticide.Chitosan not with humoral response, have affinity to cell, can be degraded by the lysozyme being extensively present in biological tissue, and can be absorbed completely by organism.In addition, chitosan has the immunoregulation effect to body, and chitosan has the series of biologic effect of activating machine system, mediation airframe systems, improves cytophagous systemic-function.Macrophage Surface also exists the receptor of bacterial polysaccharides, and chitosan is as the analog of bacterial polysaccharides, can activate by stimulating expression of macrophage, produce following reaction: promote its phagocytic function, strengthen its cooperative effect in other immunne response, thus realize the adjustment of body to T cell, NK cell and B cell, the cellullar immunologic response of mediation body and humoral immunoresponse(HI).Chitosan also can be used as products and health products additive agent, there is adjusting blood lipid, blood pressure lowering, raising immunity, regulate blood glucose and to get rid of in body the effects such as harmful heavy metal, the using value of chitosan nano in pharmacologically active causes in various fields to be paid close attention to, more and more widely especially at field of medicaments.But also there is no the pharmaceutical dosage form of chitosan-containing nanoparticle at present clinically.

Summary of the invention:

The present invention gropes through overtesting, be developed into stable performance, be easy to carry about with one and transport, the freeze-dried powder of Clinical practice potassium magnesium aspartate for injection compositions easily, reduce supplementary product consumption, improve principal agent dissolubility, ensure that the safety of clinical application.

A kind of potassium magnesium aspartate for injection composite freeze-dried powder, is characterized in that, comprise the material composition of following weight portion:

The invention allows for a kind of preparation method of potassium magnesium aspartate for injection composite freeze-dried powder, it is characterized in that, comprise the steps:

(1) preparation of chitosan nano:

1) sieve through 100 eye mesh screens after Chitosan powder being pulverized;

2) take the Chitosan powder 100g of above-mentioned mistake 100 eye mesh screen, under room temperature, (25 DEG C) add 0.1mol/L acetic acid solution 40L, and magnetic agitation makes chitosan dissolve completely, obtain chitosan acetic acid solution (C=2.5g/L);

3) pH=5.0 is regulated with 1%NaOH;

4) add 1% sodium tripolyphosphate 1667g in chitosan acetic acid solution under stirring, make chitosan/sodium tripolyphosphate mass ratio be 6:1, be cross-linked into nanoparticle by the electrostatic interaction of zwitterion;

5) by above-mentioned colloid solution 4 DEG C of high speed centrifugation (18krpm) 30min, lower sediment is collected, after pure water 3 times, in cooling juxtaposition drying under reduced pressure case, dry (less than 30 DEG C) obtain chitosan nano, moisture is lower than 2%, and particle diameter≤100nm, zeta current potential is about 15mv;

(2) preparation of potassium magnesium aspartate for injection composite freeze-dried powder:

1) take motassium magnessium aspartate 850 ~ 1700 parts according to above-mentioned prescription ratio, chitosan nano 500 ~ 1000 parts, slowly add a certain amount of 50 DEG C ~ 90 DEG C waters for injection, under preferably 60 DEG C ~ 80 DEG C conditions, be stirred to dissolving.

2) regulate pH to 8.0 with KOH, add water for injection to full dose to gained solution, the active carbon then adding amount of solution 0.05% ~ 0.15% stirs 30min, filtering active carbon, medicinal liquid, again through 0.45 μm and 0.22 μm of filtering with microporous membrane, detects intermediates content, calculates loading amount by production specification.

3) according to testing requirement fill, send into after half tamponade in freezer dryer, be cooled to-40 DEG C ± 2 DEG C, insulation 2h ~ 4h, is then evacuated to freeze drying box pressure lower than 10Pa, then with the ramp of 4 DEG C/h extremely-25 DEG C ± 2 DEG C sublimation dryings, insulation 10h, is warming up to 30 DEG C ~ 35 DEG C, insulation 2h, lyophilization terminates, outlet.

Beneficial effect of the present invention is:

Compositions of the present invention makes lyophilized injectable powder, is convenient to apply clinically, and said composition can half-life of significant prolongation medicine, the action time of prolong drug, improves the bioavailability of medicine, reduces the access times of Patient drug; The stable performance of said composition freeze-dried powder, be easy to carry about with one and transport, reducing supplementary product consumption, improve principal agent dissolubility, ensure that the safety of clinical application.

Detailed description of the invention:

Below in conjunction with embodiment, the present invention is elaborated, but the non-scope being limited to these embodiments of scope of the present invention.

The preparation (with 2000) of embodiment 1 potassium magnesium aspartate for injection composite freeze-dried powder

1. prescription

2. preparation technology

(1) take motassium magnessium aspartate 850g, potassium hydroxide 160g(residue be used as pH regulator with), magnesium oxide 70g, chitosan nano 500g, slowly add 70 DEG C of waters for injection of 7200mL, stir while adding to dissolving.

(2) pH to 8.0 is adjusted with KOH, water for injection is added to full dose to gained solution, then the active carbon adding 0.2g stirs 30min, filtering active carbon, medicinal liquid is again through 0.45 μm and 0.22 μm of filtering with microporous membrane, detect intermediates content, by every bottle of 1.0g(by motassium magnessium aspartate) calculate loading amount.

(3) according to testing requirement fill, send into after half tamponade in freezer dryer, be cooled to-40 DEG C ± 2 DEG C, insulation 2h, is then evacuated to freeze drying box pressure lower than 10Pa, then with the ramp of 4 DEG C/h extremely-25 DEG C ± 2 DEG C sublimation dryings, insulation 10h, is warming up to 30 DEG C ~ 35 DEG C, insulation 2h, lyophilization terminates, outlet.

The preparation (with 2000) of embodiment 2 potassium magnesium aspartate for injection composite freeze-dried powder

1. prescription

2. preparation technology

(1) take motassium magnessium aspartate 850g, potassium hydroxide 160g(residue be used as pH regulator with), magnesium oxide 70g, chitosan nano 500g, slowly add 70 DEG C of waters for injection of 7200mL, stir while adding to dissolving.

(2) pH to 8.0 is adjusted with KOH, water for injection is added to full dose to gained solution, then the active carbon adding 0.2g stirs 30min, filtering active carbon, medicinal liquid is again through 0.45 μm and 0.22 μm of filtering with microporous membrane, detect intermediates content, by every bottle of 1.0g(by motassium magnessium aspartate) calculate loading amount.

(3) according to testing requirement fill, send into after half tamponade in freezer dryer, be cooled to-40 DEG C ± 2 DEG C, insulation 2h ~ 4h, is then evacuated to freeze drying box pressure lower than 10Pa, then with the ramp of 4 DEG C/h extremely-25 DEG C ± 2 DEG C sublimation dryings, insulation 10h, is warming up to 30 DEG C ~ 35 DEG C, insulation 2h, lyophilization terminates, outlet.

Experimental data

One solubility experiment

Sample classification:

Sample 1: Aspartic Acid

Sample 2: chitosan

Sample 3: Aspartic Acid and chitosan physical mixture (1:0.5)

1. solubility test

Method: 25 DEG C ± 2 DEG C time, get each 0.5g of above-mentioned sample respectively, according to the form below, volume adds purified water, every the powerful jolting 30s of 5min, observe the dissolving situation in 30min, the results are shown in shown in following table 1:

Table 1 solubility test result

Note: in table, "+" expression is dissolved completely, and "-" represents insoluble, and "/" represents non-solubilizer.

Result shows: after Aspartic Acid and chitosan composite lyophilizing, dissolubility obviously increases, and shows that said composition has good solubilizing effect.

Two excipient screening experiment

1. prescription

Preparation technology: embodiment 2 simultaneously, wherein excipient type and consumption see the following form 1, and finished product observes its outward appearance, and add the redissolution of recipe quantity purified water, record dissolution time (with manual time-keeping);

Experimental result shows: with the freeze-dried powder forming of chitosan as the potassium magnesium aspartate for injection of excipient, supplementary product consumption is few, and lyophilization cycle is short, and redissolves effect due to other excipient, and clinic is applied.

More than show and describe ultimate principle of the present invention, principal character and advantage of the present invention.The technical staff of the industry should understand; the present invention is not restricted to the described embodiments; what describe in above-described embodiment and description is only preference of the present invention; be not used for limiting the present invention; without departing from the spirit and scope of the present invention; the present invention also has various changes and modifications, and these changes and improvements all fall in the claimed scope of the invention.Application claims protection domain is defined by appending claims and equivalent thereof.

Claims (1)

1. a preparation method for potassium magnesium aspartate for injection composite freeze-dried powder, is characterized in that, comprises the steps:

(1) preparation of chitosan nano:

1) sieve through 100 eye mesh screens after Chitosan powder being pulverized;

2) take the Chitosan powder 100g of above-mentioned mistake 100 eye mesh screen, add 0.1mol/L acetic acid solution 40L under room temperature, magnetic agitation, chitosan is dissolved completely, obtain chitosan acetic acid solution;

3) pH=5.0 is regulated with 1%NaOH;

4) add 1% sodium tripolyphosphate 1667g in chitosan acetic acid solution under stirring, make chitosan/sodium tripolyphosphate mass ratio be 6:1, be cross-linked into nanoparticle by the electrostatic interaction of zwitterion;

5) by colloid solution 4 DEG C of high speed centrifugation 30min, collect lower sediment, after pure water 3 times, in cooling juxtaposition drying under reduced pressure case, drying obtains chitosan nano, and moisture is lower than 2%, and particle diameter≤100nm, zeta current potential is 15mv;

(2) preparation of potassium magnesium aspartate for injection composite freeze-dried powder:

1) take motassium magnessium aspartate 850 ~ 1700 parts, chitosan nano 500 ~ 1000 parts, slowly add a certain amount of 50 DEG C ~ 90 DEG C waters for injection, under 60 DEG C ~ 80 DEG C conditions, be stirred to dissolving;

2) pH to 8.0 is regulated with KOH, water for injection is added to full dose to gained solution, then the active carbon adding amount of solution 0.05% ~ 0.15% stirs 30min, filtering active carbon, medicinal liquid is again through 0.45 μm and 0.22 μm of filtering with microporous membrane, detect intermediates content, calculate loading amount by production specification;

3) according to testing requirement fill, send into after half tamponade in freezer dryer, be cooled to-40 DEG C ± 2 DEG C, insulation 2h ~ 4h, is then evacuated to freeze drying box pressure lower than 10Pa, then with the ramp of 4 DEG C/h extremely-25 DEG C ± 2 DEG C sublimation dryings, insulation 10h, is warming up to 30 DEG C ~ 35 DEG C, insulation 2h, lyophilization terminates, outlet.