CN101785780A - Preparation of cyanocobalamine and adenosine composition and preparation method thereof - Google Patents
Preparation of cyanocobalamine and adenosine composition and preparation method thereof Download PDFInfo
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- CN101785780A CN101785780A CN201010140134A CN201010140134A CN101785780A CN 101785780 A CN101785780 A CN 101785780A CN 201010140134 A CN201010140134 A CN 201010140134A CN 201010140134 A CN201010140134 A CN 201010140134A CN 101785780 A CN101785780 A CN 101785780A
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Abstract
The invention relates to the field of the pharmaceutical preparation, in particular to a cyanocobalamine and adenosine combined pharmaceutical preparation, and comprises an oral solid preparation, injection, a freeze-dried preparation for injection and a preparation method thereof. Each unit of pharmaceutical preparation of the invention comprises 0.05-5.0mg of cyanocobalamine and 0.05-5.0mg of adenosine, wherein the weight ratio of the cyanocobalamine and the adenosine is 1:10-10:1, and the preferential weight ratio is 1:5-5:1.
Description
Technical field
The present invention belongs to field of pharmaceutical preparations, specifically, relates to the combined pharmaceutical formulation of a kind of cobamamide and adenosine, comprises oral solid formulation, injection, freeze-drying preparation for injection and preparation method thereof.
Background technology
Cobamamide, English name: Cobamamide, chemical name: 5,6-methylimidazole base-5`-deoxyadenosine base cobalt amine is a cyanogen cobalt type vitamin B
12Congener, be vitamin B
12Metabolite in vivo is a vitamin B
12One of two kinds of active coenzyme forms in vivo are growth and proliferation of cell and keep the complete necessary material of neural myelin, than vitamin B
12Have higher biological activity and bioavailability, the utilization that can directly be absorbed by the body, active strong, strong with the histiocyte affinity, drain slower; Be the important coenzyme of cell synthesizing ribonucleotide, participate in methyl conversion and folic acid metabolism in the body, promote to be reduced to tetrahydrofolic acid with methopterin; Also participate in tricarboxylic acid cycle, extremely important to the formation of lipoprotein in the neural myelin, can make the sulfydryl enzyme be in activated state, thereby participate in protein and lipid metabolism widely; Energy promotes erythrocytic growth with ripe, is complete formation spinal cord fiber and the necessary factor of maintenance digestive system epithelial cell function.Be used for vitamin B
12Lack the treatment of associated diseases, sacred disease etc.As be used for megaloblastic anemia, malnutritional anemia, anemia in pregnancy, polyneuritis, radiculitis, trigeminal neuralgia, sciatica, neural paralysis also can be used for trophism illness and lonizing radiation and drug-induced leukopenia.
Adenosine, English name Adenosine is a kind of of nucleoside, and each is made up of the ribose (ribofuranose) and the part of adenine, and the centre is linked by β-N9-glycosidic inkage (β-N9-glycosidic bond).
Adenosine is a kind of endogenous nucleoside that spreads all over human body cell, can directly enter cardiac muscle and generate adenylic acid through phosphorylation, participates in energy metabolism of myocardial, also participates in dilating coronary blood vessel, blood flow increasing simultaneously.Adenosine to cardiovascular system unify human body many other systems and organize physiological action all arranged.Adenosine is the important intermediate that is used for synthetic adenosine triphosphate (ATP), adenine, adenylic acid, vidarabine.
Adenosine is played an important role on biochemistry, comprises with adenosine triphosphate (ATP) or adenosine bis phosphoric acid (ADP) form shifting energy, or carries out signal transmission etc. with ring-type adenosine monophosphate (cAMP).This extracellular adenosine also is a kind of inhibitory nerve transmitter (inhibitory neurotransmitter), may hypnotic.
Single cobamamide component preparation is arranged at present clinically, as cobamamide sheet, injection cobamamide, and preparation such as adenosine sheet, adenosine capsule, adenosine injection liquid, injection adenosine, but its stability is all relatively poor.After the combination of cobamamide and adenosine made pharmaceutical preparation, its stability strengthened, and its drug effect strengthens greatly simultaneously.Combination preparation about cobamamide and adenosine does not appear in the newspapers as yet.
Summary of the invention
The inventor finds unexpectedly, and cobamamide and adenosine are made the combined pharmaceutical formulation that contains these two kinds of active component according to a certain ratio, can fully play their characteristics separately, has synergism simultaneously.
The invention provides the combined pharmaceutical formulation that contains cobamamide and adenosine composition, pharmaceutical preparation of the present invention can be any pharmaceutical dosage form that is fit to take, preferably oral solid formulation, injection, freeze-drying preparation for injection.Pharmaceutical preparation of the present invention can be used for treating megaloblastic anemia, malnutritional anemia, anemia in pregnancy, polyneuritis, radiculitis, trigeminal neuralgia, sciatica, neural paralysis also can be used for trophism illness and lonizing radiation and drug-induced leukopenia.
Pharmaceutical preparation of the present invention in the preparation of per unit dosage, contains cobamamide 0.05mg～5.0mg, adenosine 0.05mg～5.0mg, and wherein the weight proportion of cobamamide and adenosine is 1-10: 10-1, preferably 1-5: 5-1.
Pharmaceutical preparation of the present invention exists with unit dosage form, and described unit dosage form is meant unit dose formulations, as every of injection, and every bottle, every of oral formulations, every etc.
Pharmaceutical preparation of the present invention, can add the medicine acceptable auxiliary in case of necessity, for the preferred oral solid formulation of the present invention, described medicine acceptable auxiliary is selected from compositions such as diluent, wetting agent, binding agent, disintegrating agent, fluidizer, antiplastering aid, lubricant, color and regulator thereof, solid dispersion carrier material, antioxidant, surfactant, stabilizing agent.
Described diluent can be selected from one or more the material in starch, amylum pregelatinisatum, Icing Sugar, dextrin, lactose, microcrystalline Cellulose, mannitol, sorbitol, calcium sulfate, calcium carbonate and other the pharmaceutically acceptable diluent.Preferred starch, lactose, microcrystalline Cellulose.
Described wetting agent can be selected from the material more than zero kind or zero kind in ethanol, water and other the pharmaceutically acceptable wetting agent.
Described binding agent can be selected from one or more the material in hypromellose, ethyl cellulose, sodium carboxymethyl cellulose, methylcellulose, hyprolose, starch slurry, polyvidone, gelatin, Polyethylene Glycol, 50% to 70% sucrose solution, sodium alginate soln and other the pharmaceutically acceptable binding agent.
Described disintegrating agent can be selected from one or more the material in carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, cross-linking sodium carboxymethyl cellulose, dried starch, polyvinylpolypyrrolidone, gas-producing disintegrant and other the pharmaceutically acceptable disintegrating agent.
Described fluidizer, antiplastering aid, lubricant can be selected from one or more the material in Pulvis Talci, micropowder silica gel, magnesium stearate, polyethylene glycols, sodium laurylsulfate, magnesium laurylsulfate, hydrogenated vegetable oil and other pharmaceutically acceptable fluidizer, antiplastering aid, the lubricant.Preferred micropowder silica gel, magnesium stearate.
The optional material more than zero kind or zero kind in edible pigment, essence and other pharmaceutically acceptable color and regulator thereof of described color and regulator thereof.
Described solid dispersion carrier material is optional from polyethylene glycols, cellulose derivative, organic acid, surfactant-based, the polyvidone class, saccharide and alcohols, cellulose family, the polyacrylic resin class, cupreol, cholesterol, cholesterol ester stearic acid, tripalmitin, castor oil hydrogenated, Oleum Ricini wax, Cera Flava, the material of one or more in Brazil wax and other pharmaceutically acceptable solid dispersion carrier material, every class solid dispersion carrier material can not select or select for use one or more the material in such solid dispersion carrier material.The Brij and the poloxamer of preferred polyethylene glycols, surfactant apoplexy due to endogenous wind.
The surface of described oral solid formulation is surrounded by one to multiple layer film clothing, can add one or more the material in dispersant, plasticizer, lubricant, color and regulator thereof and other the pharmaceutically acceptable additive in the described film-coat layer coating.
Can add one or more the material in the pharmaceutically acceptable PH regulator in the described preparation.
Oral solid formulation of the present invention is selected from tablet, capsule, pill, drop pill, granule, pellet, solid dispersion, semi-solid preparation, their preparation method can adopt the preparation of galenic pharmacy routine techniques, as cobamamide, adenosine and described oral solid formulation are mixed and made into described tablet, capsule, pill, drop pill, granule, pellet, solid dispersion, semi-solid preparation with adjuvant.Whole operation is carried out under the lucifuge condition.The preparation method of tablet is to comprise pulverizing, sieve, mix, granulate as described, the method of sheeting process, the preparation method of described capsule be comprise pulverizing, sieve, the method for mixing, filling work procedure, the preparation method of described solid dispersion, semi-solid preparation be comprise pulverizing, sieve, be under the liquid condition at diluent/solid dispersion carrier material mix, the method for tabletting/filling/pill operation.
For oral solid formulation of the present invention, preferably tablet and capsule, every/of wherein said tablet and capsule contain cobamamide and adenosine 0.1mg to 10mg, wherein cobamamide: the ratio of adenosine is 5-1: 1-5.
Contain the described cobamamide of 0.02% to 20% (percentage by weight), adenosine in the described oral solid formulation, all the other are the oral solid formulation adjuvant.
The preferred injection formulation of the present invention is to be dissolved into the injection solution that forms in the suitable solvent for injection by cobamamide, adenosine; Be used for intramuscular injection or intravenous injection.
The pH value of described injection is in 3.5～7.5 scopes.Described injection also can add acceptable adjuvant, pharmaceutically acceptable pH regulator agent and/or pharmaceutically acceptable medicine with other miscellaneous function on the conventional pharmaceutical such as excipient, cosolvent, antibacterial, stabilizing agent, chelating agent, analgesics, buffer agent as required.Described injection is a solvent with water and/or other pharmaceutically acceptable organic solvent.Every in described preparation contains cobamamide and adenosine is respectively 0.05mg to 5mg, wherein cobamamide: the ratio of adenosine is 5-1: 1-5.The described solvent that contains the described cobamamide of 0.01% to 20% (percentage by weight), adenosine and surplus in the described injection.Wherein said pH regulator agent can be at least a pharmaceutically acceptable material that is used to regulate pH value, can be one or more the material in alkali compounds, buffer system and the acid, for example: sodium hydroxide, phosphate buffer, phosphoric acid, acetic acid etc.Described antibacterial can not select or for being selected from one or more the material in methyl parahydroxybenzoate, ethylparaben, propyl p-hydroxybenzoate, benzoic acid, sorbic acid and other the pharmaceutically acceptable antibacterial; Described chelating agent can not select or for being selected from one or more the material in Calcium Disodium Versenate, cyclohexanediamine four sodium acetates, N-hydroxyl diethylamine three acetic acid, diethyl triamine six acetic acid and other the pharmaceutically acceptable chelating agent
Injection of the present invention can prepare according to the galenic pharmacy routine techniques.As cobamamide and adenosine according to recipe quantity, but use the water for injection of receiving amount on the conventional pharmaceutical and/or other pharmaceutically acceptable organic solvent to be solvent, but can add cosolvent, antibacterial, stabilizing agent, chelating agent, analgesics, buffer agent acceptable adjuvant, pharmaceutically acceptable pH regulator agent on interior conventional pharmaceutical of receiving amount on the conventional pharmaceutical, and one or more the material in the pharmaceutically acceptable medicine with other miscellaneous function, be made into the solution of pH value in 3.5 to 7.5 scopes; Then gained solution is removed thermal source, filtration sterilization according to conventional method; Canned again.Product after canned can adopt conventional method to sterilize.
The method of removing thermal source, filtration sterilization of above-mentioned routine can be to add 0.01%～5% active carbon (activated carbon dosage preferred 0.01%～2%) in solution, stirs 5min～40min down at 10 ℃～60 ℃, filters decarburization; Use 0.22 μ m filtering with microporous membrane back gained filtrate then; Canned again, the circulation steam sterilization.Or under aseptic condition, described solution is filtered decarburization, also canned with 0.22 μ m filtering with microporous membrane according to preceding method.Whole operation is carried out under the lucifuge condition.
Specifically can be undertaken by following operation:
Accurately take by weighing cobamamide, adenosine and adjuvant by proportioning, add 70% to 90% of injection water recipe quantity, be stirred to dissolving fully, add to the full amount of water for injection, the control pH value is 3.5～7.5.Add active carbon, stir 10min～40min down at 10 ℃～60 ℃, decarburization filters, subsequent filtrate is extremely clear and bright with 0.22 μ m filtering with microporous membrane, gained solution is surveyed pH value and content, qualified back potting, 100 ℃ of circulation steam sterilization 15min get final product (or operation is all carried out and no longer sterilization after the potting) under aseptic condition; Whole operation is carried out under the lucifuge condition.
Freeze-drying preparation for injection of the present invention can be by the following technical solutions: the combination freeze-drying preparation for injection of described cobamamide and adenosine, solution by containing cobamamide, adenosine or cobamamide, adenosine and pharmaceutically acceptable excipient makes after lyophilization; The pH value of described solution is in 3.5～7.5 scopes.Described freeze-drying preparation for injection also can add acceptable adjuvant, pharmaceutically acceptable pH regulator agent and/or pharmaceutically acceptable medicine with other miscellaneous function on the conventional pharmaceutical such as excipient, cosolvent, antibacterial, stabilizing agent, chelating agent, analgesics, buffer agent as required.Described injection is a solvent with water and/or other pharmaceutically acceptable organic solvent.Wherein said pH regulator agent can be at least a pharmaceutically acceptable material that is used to regulate pH value, can be one or more the material in alkali compounds, buffer system and the acid, for example: sodium hydroxide, phosphate buffer, phosphoric acid, acetic acid etc.Described cosolvent is one or more the material that is selected from glycine, mannitol, lactose, sodium chloride, glucose, sorbitol, gelatin hydrolysate and other the pharmaceutically acceptable cosolvent; Described antibacterial can not select or for being selected from one or more the material in methyl parahydroxybenzoate, ethylparaben, propyl p-hydroxybenzoate, benzoic acid, sorbic acid and other the pharmaceutically acceptable antibacterial; Described chelating agent can not select or for being selected from one or more the material in Calcium Disodium Versenate, cyclohexanediamine four sodium acetates, N-hydroxyl diethylamine three acetic acid, diethyl triamine six acetic acid and other the pharmaceutically acceptable chelating agent, every in described preparation contains cobamamide and adenosine is respectively 0.05mg to 5mg, wherein cobamamide: the ratio of adenosine is 5-1: 1-5.The described solvent that contains described cobamamide of 0.01% to 20% (percentage by weight) and adenosine, the described excipient of 0% to 50% (percentage by weight) and surplus in the described solution.
Preparation method can be, cobamamide and adenosine according to recipe quantity, but use the water for injection of receiving amount on the conventional pharmaceutical and/or other pharmaceutically acceptable organic solvent to be solvent, but can add the excipient of receiving amount on the conventional pharmaceutical, cosolvent, antibacterial, stabilizing agent, chelating agent, analgesics, buffer agent is acceptable adjuvant on interior conventional pharmaceutical, pharmaceutically acceptable pH regulator agent, and one or more the material in the pharmaceutically acceptable medicine with other miscellaneous function, be made into the solution of pH value in 3.5 to 7.5 scopes; Then gained solution is removed thermal source, filtration sterilization according to conventional method; Lyophilization again.
The method of removing thermal source, filtration sterilization of above-mentioned routine can be to add 0.01%～5% active carbon (activated carbon dosage preferred 0.01%～2%) under aseptic condition in the solution, stirs 5min～40min down at 10 ℃～60 ℃, filters decarburization; Use 0.22 μ m filtering with microporous membrane back gained filtrate then; Lyophilization again.Whole operation is carried out under the lucifuge condition.
Specifically can be undertaken by following operation:
Accurately take by weighing cobamamide, adenosine and adjuvant by proportioning, add 70% to 90% of injection water recipe quantity, be stirred to dissolving fully, add to the full amount of water for injection, the control pH value is 3.5～7.5.Add active carbon, stirred 10～40 minutes down at 10 ℃～60 ℃, decarburization filters, and subsequent filtrate, is sub-packed in the cillin bottle after the inspection of semifinished product is qualified to clear and bright with 0.22 μ m filtering with microporous membrane, and lyophilization promptly; Whole operation is carried out under the lucifuge condition.
Pharmaceutical preparation of the present invention except that having synergistic advantage, also has following advantage: wherein the oral solid formulation production technology is simple, production cost is lower, carry taking convenience; Described injection drug effect is rapid, reliable effect, can be used for the patient of first aid and unsuitable oral administration; Described freeze-drying preparation for injection drug effect is rapid, reliable effect, can be used for the patient of first aid and unsuitable oral administration, and the holding time is long, good stability, few side effects.
The specific embodiment
Below will the invention will be further described by embodiment, these descriptions are not that content of the present invention is done further qualification.One skilled in the art will understand that the equal replacement that technical characterictic of the present invention is done, or corresponding the improvement, still belong within protection scope of the present invention.
Embodiment
Cobamamide in following examples is provided by North China pharmacy Wei Keda company limited, and adenosine is provided by Xinfeng, Xinxiang City Fine Chemical Co., Ltd, and adjuvant is commercially available product.
Embodiment 1
| Prescription 1 | Prescription 2 | Prescription 3 | |
| Cobamamide | ??0.05g | ??0.5g | ?5g |
| Adenosine | ??0.05g | ??0.5g | ??5g |
| Starch | ??60.0g | ??60.0g | ??60.0g |
| Microcrystalline Cellulose | ??60.0g | ??60.0g | ??60.0g |
| Carboxymethyl starch sodium | ??6.0g | ??6.0g | ??6.0g |
| Hyprolose | ??6.0g | ??6.0g | ??6.0g |
| Micropowder silica gel | ??2.0g | ??2.0g | ??2.0g |
| Magnesium stearate | ??2.0g | ??2.0g | ??2.0g |
| Sodium lauryl sulphate | ??1.5g | ??1.5g | ??1.5g |
Make 1000 slices/
Preparation technology
Remarks: following operation is all carried out under the lucifuge condition.
A. take by weighing cobamamide, the adenosine of recipe quantity, cross 80 mesh sieves,
B. take by weighing the adjuvant mix homogeneously of recipe quantity, cross 80 mesh sieve mixings,
C. with adjuvant and cobamamide, adenosine increasing progressively the abundant mixing of dilution method,
D. with " c " gained granulating mixture,
E. with " d " gained granule tabletting, wrap film-coat, promptly get the compounded plate of cobamamide and adenosine
Or with " c " gained mixture with direct powder pressing method tabletting, promptly get the compounded plate of cobamamide and adenosine
Or " d " gained granule directly is filled to Capsules, promptly get the complex capsule of cobamamide and adenosine.
Embodiment 2
| Prescription 1 | Prescription 2 | Prescription 3 | |
| Cobamamide | ??0.05g | ??0.1g | ??0.5g |
| Prescription 1 | Prescription 2 | Prescription 3 | |
| Adenosine | ??0.01g | ??0.02g | ??0.1g |
| Water for injection | To 1000ml | To 1000ml | To 1000ml |
Make 1000
Preparation technology
Remarks: following operation is all carried out under the lucifuge condition.
A. accurately take by weighing cobamamide, adenosine by prescription, add 70% to 90% of injection water recipe quantity, be stirred to dissolving fully, add to the full amount of water for injection, the control pH value is 3.5～7.5;
B. add 0.01%～0.20% active carbon in " a " gained solution, stir 5min～40min down at 10 ℃～60 ℃, filter decarburization, reuse 0.22 μ m filtering with microporous membrane is to clear and bright;
C. " b " gained solution is surveyed pH value and content, is sub-packed in 1000 ampoules after qualified, seals, and 100 ℃ of circulation steam sterilization 15min promptly get combination injection, J, K, the L of a kind of cobamamide and adenosine.
D. add 0.01%～0.20% active carbon in " a " gained solution, stir 5min～40min down at 10 ℃～60 ℃, filter decarburization, reuse 0.22 μ m filtering with microporous membrane is to clear and bright;
E. " d " gained solution is surveyed pH value and content, is sub-packed in 1000 ampoules after qualified, seals (" d " " e " operation is all carried out under aseptic condition), promptly gets the combination injection of cobamamide and adenosine.
Embodiment 3
| Prescription 1 | Prescription 2 | Prescription 3 | |
| Cobamamide | ??0.05g | ??0.1g | ??0.5g |
| Adenosine | ??0.01g | ??0.02g | ??0.1g |
| Mannitol | ??100g | ??100g | ??100g |
| Water for injection | To 1000ml | To 1000ml | To 1000ml |
Make 1000
Preparation technology
Remarks: following operation is all carried out under the lucifuge condition.
A. accurately take by weighing cobamamide, adenosine and adjuvant by prescription, add 70% to 90% of injection water recipe quantity, be stirred to dissolving fully, add to the full amount of water for injection, the control pH value is 3.5～7.5;
B. add 0.01%～0.20% active carbon in " a " gained solution, stir 5min～40min down at 10 ℃～60 ℃, filter decarburization, reuse 0.22 μ m filtering with microporous membrane is to clear and bright;
C. " b " gained solution is surveyed pH value and content, be sub-packed in 1000 cillin bottles after qualified, and lyophilization, gland promptly gets the combination freeze-drying preparation for injection of cobamamide and adenosine.
Embodiment 4
The test that keeps sample for a long time of cobamamide and adenosine composition lyophilized formulations
(25 ℃ ± 2 ℃, RH60% ± 10%, specification: 1mg)
| Acidity | 6.2 | 6.0 | 6.4 | 6.3 | 6.3 |
| Content (%) | 108.3 | 109.7 | 107.8 | 108.6 | 109.1 |
| Lot number 1002012 | 0 | 3 | 6 | 9 | 12 |
| Character | Pale red lyophilizing block, soluble in water. | Pale red lyophilizing block, soluble in water. | Pale red lyophilizing block, soluble in water. | Pale red lyophilizing block, soluble in water. | Pale red lyophilizing block, soluble in water. |
| Hydroxocobalamine | 0.89 | 0.93 | 0.87 | 0.91 | 0.83 |
| Loss on drying (%) | 0.8 | 0.6 | 0.6 | 0.7 | 0.9 |
| Acidity | 6.7 | 6.5 | 6.8 | 6.6 | 6.8 |
| Content (%) | 102.3 | 104.7 | 105.8 | 103.6 | 104.1 |
| Lot number 1002013 | 0 | 3 | 6 | 9 | 12 |
| Character | Pale red lyophilizing block, soluble in water. | Pale red lyophilizing block, soluble in water. | Pale red lyophilizing block, soluble in water. | Pale red lyophilizing block, soluble in water. | Pale red lyophilizing block, soluble in water. |
| Hydroxocobalamine | 0.96 | 0.99 | 0.89 | 0.95 | 0.94 |
| Loss on drying (%) | 0.7 | 0.6 | 0.9 | 0.5 | 0.7 |
| Acidity | 6.5 | 6.2 | 6.4 | 6.9 | 6.4 |
| Content (%) | 101.25 | 102.16 | 102.94 | 103.05 | 101.95 |
Claims (10)
1. combined pharmaceutical formulation that contains cobamamide and two kinds of active component of adenosine.
2. pharmaceutical preparation according to claim 1 is characterized in that described cobamamide, adenosine are the salt of this cobamamide, adenosine or this cobamamide, adenosine or this cobamamide, a kind of or this cobamamide of the single enantiomer of adenosine, a kind of salt of the single enantiomer of adenosine.
3. pharmaceutical preparation according to claim 1 is characterized in that in the preparation of per unit dosage, contains cobamamide 0.05mg～5.0mg, adenosine 0.05mg～5.0mg, wherein cobamamide: the ratio of adenosine is 1-10: 10-1.
4. pharmaceutical preparation according to claim 1 is characterized in that described preparation is selected from: oral solid formulation and injection.
5. pharmaceutical preparation according to claim 1 is characterized in that described oral solid formulation is selected from tablet, capsule, pill, drop pill, granule, pellet, solid dispersion, semi-solid preparation; Described injection is selected from injection and freeze-drying preparation for injection.
6. pharmaceutical preparation according to claim 5, it is characterized in that also containing in case of necessity the medicine acceptable auxiliary, described adjuvant is pharmaceutically acceptable preparation adjuvant, for oral solid formulation, described adjuvant is selected from diluent, wetting agent, binding agent, disintegrating agent, fluidizer, antiplastering aid, lubricant, color, fragrant, flavor and regulator thereof, the solid dispersion carrier material, antioxidant, surfactant, stabilizing agent, the material of one or more in the PH regulator, every kind of adjuvant can not select or select for use one or more the material in this kind adjuvant;
Be selected from cosolvent, antibacterial, stabilizing agent, chelating agent, analgesics, buffer agent, pharmaceutically acceptable pH regulator agent for injection and the described adjuvant of freeze-drying preparation for injection, and one or more the material in the pharmaceutically acceptable medicine with other miscellaneous function, wherein said freeze-drying preparation for injection can be selected pharmaceutically acceptable excipient for use.
7. pharmaceutical preparation according to claim 6, it is characterized in that, described antibacterial can not select or for being selected from one or more the material in methyl parahydroxybenzoate, ethylparaben, propyl p-hydroxybenzoate, benzoic acid, sorbic acid and other the pharmaceutically acceptable antibacterial, and described chelating agent can not select or for being selected from one or more the material in Calcium Disodium Versenate, cyclohexanediamine four sodium acetates, N-hydroxyl diethylamine three acetic acid, diethyl triamine six acetic acid and other the pharmaceutically acceptable chelating agent; Described pH regulator agent can be at least a pharmaceutically acceptable material that is used to regulate pH value, it can be one or more the material in alkali compounds, buffer system and the acid, as: sodium hydroxide, phosphate buffer, phosphoric acid, acetic acid etc., described excipient are one or more the materials that is selected from glycine, mannitol, lactose, sodium chloride, glucose, sorbitol, gelatin hydrolysate and other the pharmaceutically acceptable excipient.
8. the preparation method of pharmaceutical preparation according to claim 4 comprises the step with cobamamide and adenosine and pharmaceutically acceptable mixed with excipients.
9. preparation method according to claim 8, it is characterized in that wherein the preparation method of oral solid formulation can adopt direct powder pressing method, wherein freeze-drying preparation for injection will be through containing the solution of cobamamide and adenosine, or the solution of cobamamide and adenosine and pharmaceutically acceptable excipient, carry out cryodesiccated step; Wherein injection will be through containing cobamamide and adenosine is dissolved into the step of making solution in the solvent for injection; The pH value of described solution and described injection is in 3.5 to 7.5 scopes, and described solution and described injection are solvent with water and/or other pharmaceutically acceptable organic solvent; Can contain acceptable adjuvant on the conventional pharmaceutical that comprises cosolvent, antibacterial, stabilizing agent, chelating agent, analgesics, buffer agent, pharmaceutically acceptable pH regulator agent in described injection and the freeze-drying preparation for injection, and one or more the material in the pharmaceutically acceptable medicine with other miscellaneous function.
10. preparation method according to claim 8 is characterized in that the preparation method of described injection and freeze-drying preparation for injection can may further comprise the steps:
(1) preparation contains cobamamide, adenosine, and its pH value is 3.5 to 7.5 solution;
(2) step (1) gained solution is removed pyrogen, filtration sterilization according to conventional method;
(3) potting step (2) gained solution; Or lyophilization step (2) gained solution.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103284961A (en) * | 2013-06-20 | 2013-09-11 | 门毅 | Preparing method of cobamamide freeze-drying formulation for injection |
| CN105267161A (en) * | 2015-11-24 | 2016-01-27 | 河北智同生物制药有限公司 | Cobamamide freeze-drying preparation composition for injection and preparing method thereof |
| EA030298B1 (en) * | 2011-09-12 | 2018-07-31 | Ворлд Медысыне Илач Санайи Ве Тиджарет Лимитед Ширкети | Lyophilized preparation of atp and complex of group b vitamins and atp and complex of group b vitamins in the form of injections |
| CN111671912A (en) * | 2020-06-22 | 2020-09-18 | 上海上药第一生化药业有限公司 | Composition containing cobamamide, freeze-dried powder, preparation method thereof and injection medicine |
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| CN101184496A (en) * | 2005-05-27 | 2008-05-21 | 兴和株式会社 | Pharmaceutical preparation for recovery from fatigue |
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