CN103536623A - 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, relate in particular 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, in tricarboxylic acid cycle, plays an important role.Meanwhile, Aspartic Acid is also participated in ornithine cycle, promotes the metabolism of ammonia and carbon dioxide, makes it to generate carbamide, the content of ammonia and carbon dioxide in reduction blood.Aspartic Acid is stronger to cellular affinity, and it forms firm potassium salt, magnesium salt after being combined with potassium ion, magnesium ion, thereby the carrier that makes Aspartic Acid become potassium magnesium ion enters in body cell this this two kinds of ions.Motassium magnessium aspartate participates in ornithine cycle, makes NH3 and CO2 generate carbamide and reaches Detoxication; It has following important physiological function: participating in tricarboxylic acid cycle, promote energy metabolism, is the catalyst of the synthetic decomposition of high-energy phosphate compound; Participation nucleotide generates, and is the important substance of cytothesis and regeneration; Can promote the excretion of bile and bile pigments, have the effects such as row is yellow, minimizing liver fat, increase hepatic glycogen; Promote that T lymphocyte Development And Differentiation is 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 are poor, these shortcomings are brought 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, has fundamentally solved 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 with cationic property of unique discovery up to now, chitosan is widespread in nature in unicellular lower eukaryote mushroom, the cell of algae, the shell of a joint animal shrimp, Eriocheir sinensis, insecticide etc.Chitosan not with humoral response, cell is had to affinity, the lysozyme that can be extensively present in biological tissue is degraded, and can be absorbed completely by organism.In addition, chitosan has the immunoregulation effect to body, and chitosan has the series of biologic of activating machine system, mediation airframe systems and learns effect, improves cytophagous systemic-function.Macrophage Surface 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, thereby realize the adjusting of body to T cell, NK cell and B cell, cellullar immunologic response and the humoral immunoresponse(HI) of mediation body.Chitosan also can be used as products and health products additive agent, there is the blood fat of adjusting, blood pressure lowering, raising immunity, regulate blood glucose and get rid of the effects such as the interior harmful heavy metal of body, the using value of chitosan nano aspect pharmacologically active caused more and more widely and paid close attention in various fields, especially at field of medicaments.But also there is no clinically the pharmaceutical dosage form of chitosan-containing nanoparticle at present.

Summary of the invention:

The present invention gropes through overtesting, is developed into stable performance, is easy to carry about with one and the freeze-dried powder of transportation, clinical potassium magnesium aspartate for injection compositions easy to use, reduces supplementary product consumption, improves principal agent dissolubility, has guaranteed the safety of clinical application.

A composite freeze-dried powder, is characterized in that, the material composition that comprises following weight portion:

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

(1) preparation of chitosan nano:

1) will after the pulverizing of chitosan powder, through 100 eye mesh screens, sieve;

2) take the chitosan powder 100g of above-mentioned mistake 100 eye mesh screens, under room temperature, (25 ℃) add 0.1mol/L acetic acid solution 40L, and magnetic agitation is dissolved chitosan completely, obtains chitosan acetic acid solution (C=2.5g/L);

3) with 1%NaOH, regulate pH=5.0;

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

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

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

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

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

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

Beneficial effect of the present invention is:

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

The specific embodiment:

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

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

1. write out a prescription

2. preparation technology

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

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

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

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

1. write out a prescription

2. preparation technology

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

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

(3) according to testing requirement fill, after half tamponade, send in freezer dryer, be cooled to-40 ℃ ± 2 ℃, insulation 2h～4h, is then evacuated to freeze drying box pressure lower than 10Pa, then the speed with 4 ℃/h is warming up to-25 ℃ ± 2 ℃ sublimation dryings, insulation 10h, is warming up to 30 ℃～35 ℃, insulation 2h, lyophilization finishes, 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: in the time of 25 ℃ ± 2 ℃, get respectively each 0.5g of above-mentioned sample, according to the form below, volume adds purified water, every the powerful jolting 30s of 5min, observes the dissolving situation in 30min, the results are shown in shown in following table 1:

Table 1 solubility test result

Note: in table, "+" represents to dissolve completely, and "-" represents insoluble, and "/" represents not 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. write out a prescription

Preparation technology: embodiment 2 simultaneously, wherein excipient type and consumption see the following form 1, and finished product is observed its outward appearance, and adds recipe quantity purified water to redissolve, and records dissolution time (with manual time-keeping);

Experimental result shows: the freeze-dried powder forming with chitosan as the potassium magnesium aspartate for injection of excipient, and 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 described 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 in above-described embodiment and description, describe 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.The claimed scope of the present invention is defined by appending claims and equivalent thereof.

Claims (2)

1. a potassium magnesium aspartate for injection composite freeze-dried powder, is characterized in that, the material composition that comprises following weight portion:

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

(1) preparation of chitosan nano:

1) will after the pulverizing of chitosan powder, through 100 eye mesh screens, sieve;

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

3) with 1%NaOH, regulate pH=5.0;

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

5) by 4 ℃ of high speed centrifugation 30min of above-mentioned colloid solution, collect lower sediment, with after pure water washing 3 times, the dry chitosan nano that obtains in cooling juxtaposition drying under reduced pressure case, moisture is lower than 2%, particle diameter≤100nm, zeta current potential is about 15mv;

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

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

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

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