CN101856325A - Hydrochloric acid melphalan injection liquid and preparation method thereof - Google Patents
Hydrochloric acid melphalan injection liquid and preparation method thereof Download PDFInfo
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- CN101856325A CN101856325A CN201010198648A CN201010198648A CN101856325A CN 101856325 A CN101856325 A CN 101856325A CN 201010198648 A CN201010198648 A CN 201010198648A CN 201010198648 A CN201010198648 A CN 201010198648A CN 101856325 A CN101856325 A CN 101856325A
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Abstract
The invention relates to the technical field of medicine preparations. The hydrochloric acid melphalan is very unstable in water, and a large amount of medicine degrades after several hours to generate impurities causing toxic or side effect, so the hydrochloric acid melphalan is not suitable for being prepared into medicine water solution to be stored for a long time. The invention provides stable hydrochloric acid melphalan injection liquid, which consists of hydrochloric acid melphalan, injection-use solvents and pH value regulating agents, wherein the injection-use solvents are anhydrous solvents obtained through dewatering treatment. The hydrochloric acid melphalan injection liquid of the invention has the advantages of stable preparation, low cost, autoclaving capability and small toxic or side effect.
Description
Technical field
The present invention relates to technical field of medicine, be specifically related to a kind of hydrochloric acid melphalan injection and preparation method thereof.
Background technology
Melphalan, common name: alkeran, L-Sarcolysinum, Melphalan, L-Sarcolysinum, L-sarcolysin, L-Sarcolysinum; English name: Melphalan, L-Sarcolysine, Alkeran, L-PAM, CB3025; Chemical name: L-3{ is to [two (2-chloroethyl) amido] phenyl } alanine; Molecular formula: C
13H
18O
2N
2C
12Melphalan is water insoluble, and less stable.In order to improve its stability and water solublity,, be prepared into hydrochloric acid melphalan with itself and hydrochloric acid salify.Hydrochloric acid melphalan be white to buff powder, be slightly soluble in water, be soluble in organic solvents such as dehydrated alcohol, to light, heat and unstable under moisture conditions.
Hydrochloric acid melphalan is the levo form of melphalan, is a kind of alkylating agent, and non-specific antineoplastic agent of genus cycle by with DNA guanine N7 alkylation reaction taking place, makes DNA that interlinkage take place, and stops DNA to duplicate and brings into play antitumor action.Because the specificity of its structure, it can initiatively be entered in the tumor cell and play a role, cause death of neoplastic cells.Its antitumor spectrum is wide, be used for the treatment of breast carcinoma, ovarian cancer, chronic lymphocytic, granulocyte leukemia, malignant lymphoma and multiple myeloma etc. clinically, arterial perfusion can also be treated limb malignant tumor, as malignant melanoma, osteosarcoma and soft tissue sarcoma etc., it is widely used, determined curative effect.
At present, existing melphalan tablet applications is in clinical.In order further to improve bioavailability, improve curative effect, people make great efforts it is developed to injection preparation.Because hydrochloric acid melphalan utmost point unstability in water, medicine is degraded in a large number after a few hours, produces the impurity that causes toxic and side effects, so be not suitable for it directly is mixed with the pharmaceutical aqueous solution long-term storage.People just can take into account naturally according to convention it are prepared into lyophilized injectable powder in order to overcome the deficiency of the long-time and water contact stabilization difference of hydrochloric acid melphalan.Crinis Carbonisatus such as Ye Dong are understood a kind of hydrochloric acid melphalan lyophilized injectable powder (CN200910033896.2), and this invention promptly is that it is prepared into freeze-dried powder, think that stability has obtained improving greatly.Yet it is known in this field, freeze-dried powder is not absolute water-less environment, still contains a certain amount of moisture content, points out that in the embodiment 11 of this patent application the freeze-dried powder water content is 0.39-0.67% yet, medicine is in dampness all the time, and long-term storage stability is relatively poor.In addition, the preparation freeze-dried powder consuming time long, power consumption is huge, causes cost significantly to increase.
Summary of the invention
The objective of the invention is to develop a kind of stable, economic hydrochloric acid melphalan injection liquid, a kind of hydrochloric acid melphalan injection liquid of not water content especially is provided.
The invention provides a kind of hydrochloric acid melphalan injection liquid, be made up of hydrochloric acid melphalan, solvent for injection and pH value regulator, concrete component and consumption are as follows:
Wherein solvent for injection is the anhydrous solvent by obtaining after the processed.
A kind of hydrochloric acid melphalan injection liquid of the present invention, wherein hydrochloric acid melphalan content is 1-100 (mg/ml); Preferred content is 5-80 (mg/ml).
A kind of hydrochloric acid melphalan injection liquid of the present invention, wherein said pH value regulator are selected from a kind of in citric acid, lactic acid, malic acid, hydrochloric acid, the acetic acid, regulate pH value to 2-7; A kind of in optimization citric acid, the hydrochloric acid preferably regulates pH value to 4-6.
A kind of hydrochloric acid melphalan injection liquid of the present invention, wherein said solvent for injection is selected from dehydrated alcohol, PEG400, propylene glycol, N, the mixture of one or more in the N dimethyl acetylamide; A kind of in preferred dehydrated alcohol, the PEG400 or both mixture.
The present invention also provides a kind of preparation method of hydrochloric acid melphalan injection liquid, and this method is to realize as follows:
Earlier solvent for injection is carried out processed; The hydrochloric acid melphalan that takes by weighing formula ratio then 25-80 ℃ of following heated and stirred dissolving, is settled to full dose with the dehydration solvent for injection to an amount of dehydration solvent for injection; Regulate pH value to 2-7 with the pH value regulator; Adding the bulking value percentage composition is the needle-use activated carbon of 0.01%-2% (grams per milliliter), and absorption is 15-120 minute under 25-80 ℃ heating-up temperature; Filtration, packing, seal, sterilize, promptly get hydrochloric acid melphalan injection liquid.
The preparation method of above-mentioned hydrochloric acid melphalan injection liquid, processed wherein is to adopt the dehydrant dehydration.
Adopt the dehydrant processed specifically: dehydrant is added in the solvent for injection, stir dehydration 10-120 minute, filter, obtain the solvent for injection that dewaters; Wherein dehydrant is selected from a kind of in anhydrous sodium sulfate, anhydrous calcium chloride, the anhydrous magnesium sulfate, and consumption is 0.5-15% (grams per milliliter); Preferred anhydrous sodium sulfate, preferable amount is 0.5-5% (grams per milliliter); Wherein said stirring dewatering time, preferred 15-90 minute.
The preparation method of a kind of hydrochloric acid melphalan injection liquid of the present invention, described heated and stirred solution temperature, preferred 25-55 ℃.
The preparation method of a kind of hydrochloric acid melphalan injection liquid of the present invention, described needle-use activated carbon absorbing process, the preferred 0.5-1.5% of activated carbon dosage (grams per milliliter), the preferred 25-45 of adsorption temp ℃, the preferred 20-40 of adsorption time minute.
The preparation method of a kind of hydrochloric acid melphalan injection liquid of the present invention, described filtration is to adopt microporous filter membrane or bag type filter to filter.
The preparation method of a kind of hydrochloric acid melphalan injection liquid of the present invention, described sterilization is to adopt high steam, flowing steam or cross 0.22 μ m microporous filter membrane sterilization, wherein high temperature sterilize temperature 100-121 ℃, time 8-45 minute.
Hydrochloric acid melphalan injection liquid of the present invention has the following advantages:
1. preparation stabilization:, effectively overcome the deficiency of medicine less stable under wet environment, thereby guaranteed the stability of injection long-term storage because this injection is a kind of no water injection that obtains by processed.
2. cost is low: this injection is the solution that forms by common prepared such as simple dissolving, filtration, sterilizations, need not lyophilizing, has overcome power consumption, big deficiency consuming time in the freeze-dry process preparation process, greatly reduces patient's drug cost.
3. drug loading is big: this injection is hydrochloric acid melphalan directly to be dissolved in the solvent for injection be prepared from, and as the dissolving of hydrochloric acid melphalan in dehydrated alcohol rapidly, and dissolubility is greater than 40mg/m; And in water, separate than indissoluble, need means such as assisting ultrasonic heating could dissolve, and dissolubility is less than 3mg/ml, so often dissolve when redissolving with normal saline after the aqueous solution lyophilizing insufficiently, need the smooth redissolution of reduction drug loading ability lyophilized powder, cause drug loading less.
4. hot pressing sterilization: because this injection is no water injection, can pass through pressure sterilizing, medicament contg does not have significant change before and after the sterilization, thereby guarantees the aseptic requirement of injection.All can not pass through pressure sterilizing and contain water injection, freeze-dried powder,, contain the aseptic that water injection and freeze-dried powder can not guarantee injection because medicament contg declines to a great extent before and after its sterilization.
5. toxic and side effects is little: because this injection stability improves greatly, the catabolite of being degraded in preparation and long-term storage process is less, thereby has effectively reduced because the caused toxic and side effects of catabolite.
The specific embodiment
Describe the present invention below in conjunction with embodiment, but enforcement of the present invention is not limited only to this.
Embodiment 1 hydrochloric acid melphalan injection liquid
Take by weighing anhydrous sodium sulfate 4 grams, to 200 milliliters dehydrated alcohol, stir dehydration 15 minutes, filter, dehydrated alcohol must dewater; Take by weighing hydrochloric acid melphalan 1.0 grams, to 95 milliliters of dehydration dehydrated alcohol,, be settled to 100 milliliters of full doses with the dehydration dehydrated alcohol then 25 ℃ of following heated and stirred dissolvings; With the Fructus Citri Limoniae acid for adjusting pH value is 4.5; Add 0.5 gram needle-use activated carbon, 45 ℃ adsorbed 30 minutes down; Use filtering with microporous membrane, packing is sealed, and 121 ℃ of sterilizations of high steam 15 minutes promptly get hydrochloric acid melphalan injection liquid.
Embodiment 2 hydrochloric acid melphalan injection liquids
Take by weighing anhydrous sodium sulfate 30 grams, to 200 milliliters propylene glycol, stir dehydration 10 minutes, filter, propylene glycol must dewater; Take by weighing hydrochloric acid melphalan 2.5 grams, to 90 milliliters of dehydration propylene glycol,, be settled to 100 milliliters of full doses with the dehydration propylene glycol then 80 ℃ of following heated and stirred dissolvings; Regulating pH value with hydrochloric acid is 6.3; Add 2 gram needle-use activated carbons, 60 ℃ adsorbed 20 minutes down; Use filtering with microporous membrane, packing is sealed, and 121 ℃ of sterilizations of high steam 15 minutes promptly get hydrochloric acid melphalan injection liquid.
Embodiment 3 hydrochloric acid melphalan injection liquids
Take by weighing anhydrous calcium chloride 20 grams, to 200 milliliters PEG400, stir dehydration 60 minutes, filter, PEG400 must dewater; Take by weighing hydrochloric acid melphalan 0.5 gram, to 95 milliliters of dehydration PEG400s,, be settled to 100 milliliters of full doses with the dehydration PEG400 then 70 ℃ of following heated and stirred dissolvings; Regulating pH value with lactic acid is 3.5; Add 1.2 gram needle-use activated carbons, 80 ℃ adsorbed 15 minutes down; Use filtering with microporous membrane, packing is sealed, and 115 ℃ of sterilizations of high steam 30 minutes promptly get hydrochloric acid melphalan injection liquid.
Embodiment 4 hydrochloric acid melphalan injection liquids
Take by weighing anhydrous magnesium sulfate 1.0 grams,, in the N dimethyl acetylamide, stir dehydration 90 minutes, filter the N that to dewater, N dimethyl acetylamide to 200 milliliters N; Take by weighing hydrochloric acid melphalan 4.0 grams, to 80 milliliters of dehydration N, in the N dimethyl acetylamide, 35 ℃ of following heated and stirred dissolvings, with dehydration N, the N dimethyl acetylamide is settled to 100 milliliters of full doses then; With the Fructus Mali pumilae acid for adjusting pH value is 5.2; Add 0.8 gram needle-use activated carbon, 40 ℃ adsorbed 60 minutes down; With 0.22 μ m filtering with microporous membrane, packing is sealed, and promptly gets hydrochloric acid melphalan injection liquid.
Embodiment 5 hydrochloric acid melphalan injection liquids
Take by weighing anhydrous magnesium sulfate 8 gram, to the mixed liquor of 100 milliliters dehydrated alcohol and 100 milliliters PEG400, stir dehydration 70 minutes, filtration, mixed solvent must dewater; Take by weighing hydrochloric acid melphalan 1.5 grams, to 95 milliliters of dehydration mixed solvents,, be settled to 100 milliliters of full doses with the dehydration mixed solvent then 40 ℃ of following heated and stirred dissolvings; With the Fructus Citri Limoniae acid for adjusting pH value is 4.0; Add 1.0 gram needle-use activated carbons, 35 ℃ adsorbed 40 minutes down; Use filtering with microporous membrane, packing is sealed, and 100 ℃ of sterilizations of flowing steam 45 minutes promptly get hydrochloric acid melphalan injection liquid.
Embodiment 6 hydrochloric acid melphalan injection liquids
Take by weighing anhydrous calcium chloride 6 gram, to 60 milliliters dehydrated alcohol, 120 milliliters propylene glycol, 20 milliliters the mixed liquor of PEG400, stir dehydration 50 minutes, filter, mixed solvent must dewater; Take by weighing hydrochloric acid melphalan 2.0 grams, to 90 milliliters of dehydration mixed solvents,, be settled to 100 milliliters of full doses with the dehydration mixed solvent then 50 ℃ of following heated and stirred dissolvings; With the Fructus Citri Limoniae acid for adjusting pH value is 2.0, adds 1.5 gram needle-use activated carbons, and 30 ℃ adsorbed 35 minutes down; Filter with bag type filter, packing is sealed, and 121 ℃ of sterilizations of high steam 8 minutes promptly get hydrochloric acid melphalan injection liquid.
Embodiment 7 hydrochloric acid melphalan injection liquids
Take by weighing anhydrous sodium sulfate 2.0 grams, to 200 milliliters PEG400, stir dehydration 50 minutes, filter, PEG400 must dewater; Take by weighing hydrochloric acid melphalan 1.0 grams, to 95 milliliters of dehydration PEG400s,, be settled to 100 milliliters of full doses with the dehydration PEG400 then 55 ℃ of following heated and stirred dissolvings; Regulating pH value with acetic acid is 5.1; Add 0.5 gram needle-use activated carbon, 25 ℃ adsorbed 40 minutes down; Use filtering with microporous membrane, packing is sealed, and 121 ℃ of sterilizations of high steam 10 minutes promptly get hydrochloric acid melphalan injection liquid.
Embodiment 8 hydrochloric acid melphalan injection liquids
Take by weighing anhydrous sodium sulfate 9 gram, to 20 milliliters dehydrated alcohol, 180 milliliters PEG400, stir dehydration 60 minutes, filter, mixed solvent must dewater; Take by weighing hydrochloric acid melphalan 0.1 gram, to 95 milliliters of dehydration mixed solvents,, be settled to 100 milliliters of full doses with the dehydration mixed solvent then 40 ℃ of following heated and stirred dissolvings; With the Fructus Mali pumilae acid for adjusting pH value is 4.2; Add 0.9 gram needle-use activated carbon, 65 ℃ adsorbed 15 minutes down; Use filtering with microporous membrane, packing is sealed, and 121 ℃ of sterilizations of high steam 15 minutes promptly get hydrochloric acid melphalan injection liquid.
Embodiment 9 hydrochloric acid melphalan injection liquids
Take by weighing anhydrous sodium sulfate 3.0 grams, to 200 milliliters dehydrated alcohol, stir dehydration 10 minutes, filter, dehydrated alcohol must dewater; Take by weighing hydrochloric acid melphalan 3.0 grams, to 90 milliliters of dehydration dehydrated alcohol,, be settled to 100 milliliters of full doses with the dehydration dehydrated alcohol then 25 ℃ of following heated and stirred dissolvings; With the Fructus Citri Limoniae acid for adjusting pH value is 3.5; Add 0.5 gram needle-use activated carbon, 25 ℃ adsorbed 30 minutes down; Use filtering with microporous membrane, packing is sealed, and 121 ℃ of sterilizations of high steam 15 minutes promptly get hydrochloric acid melphalan injection liquid.
Embodiment 10 hydrochloric acid melphalan injection liquids
Take by weighing anhydrous sodium sulfate 10 grams, to 200 milliliters dehydrated alcohol, stir dehydration 15 minutes, filter, dehydrated alcohol must dewater; Take by weighing hydrochloric acid melphalan 3.5 grams, to 95 milliliters of dehydration dehydrated alcohol,, be settled to 100 milliliters of full doses with the dehydration dehydrated alcohol then 40 ℃ of following heated and stirred dissolvings; Regulating pH value with hydrochloric acid is 2.5; Add 1.0 gram needle-use activated carbons, 40 ℃ adsorbed 20 minutes down; Filter with bag type filter, packing is sealed, and 121 ℃ of sterilizations of high steam 15 minutes promptly get hydrochloric acid melphalan injection liquid.
Embodiment 11 hydrochloric acid melphalan injection liquids
Take by weighing anhydrous sodium sulfate 1.6 grams, to 200 milliliters dehydrated alcohol, stir dehydration 80 minutes, filter, dehydrated alcohol must dewater; Take by weighing hydrochloric acid melphalan 4.0 grams, to 80 milliliters of dehydration dehydrated alcohol,, be settled to 100 milliliters of full doses with the dehydration dehydrated alcohol then 50 ℃ of following heated and stirred dissolvings; Regulating pH value with acetic acid is 3.0; Add 1.5 gram needle-use activated carbons, 25 ℃ adsorbed 60 minutes down; Use filtering with microporous membrane, packing is sealed, and 121 ℃ of sterilizations of high steam 15 minutes promptly get hydrochloric acid melphalan injection liquid.
Embodiment 12 hydrochloric acid melphalan injection liquids
Take by weighing anhydrous sodium sulfate 30 grams, to 200 milliliters dehydrated alcohol, stir dehydration 15 minutes, filter, dehydrated alcohol must dewater; Take by weighing hydrochloric acid melphalan 4.0 grams, to 95 milliliters of dehydration dehydrated alcohol,, be settled to 100 milliliters of full doses with the dehydration dehydrated alcohol then 45 ℃ of following heated and stirred dissolvings; With the Fructus Citri Limoniae acid for adjusting pH value is 7.0; Add 1.4 gram needle-use activated carbons, 45 ℃ adsorbed 25 minutes down; With 0.22 μ m filtering with microporous membrane, packing is sealed, and promptly gets hydrochloric acid melphalan injection liquid.
Embodiment 13 hydrochloric acid melphalan injection liquids
Take by weighing anhydrous calcium chloride 1.0 grams, to 200 milliliters dehydrated alcohol, stir dehydration 15 minutes, filter, dehydrated alcohol must dewater; Take by weighing hydrochloric acid melphalan 2.0 grams, to 95 milliliters of dehydration dehydrated alcohol,, be settled to 100 milliliters of full doses with the dehydration dehydrated alcohol then 40 ℃ of following heated and stirred dissolvings; With the Fructus Citri Limoniae acid for adjusting pH value is 5.0; Add 0.05 gram needle-use activated carbon, 50 ℃ adsorbed 20 minutes down; Use filtering with microporous membrane, packing is sealed, and 100 ℃ of sterilizations of flowing steam 45 minutes promptly get hydrochloric acid melphalan injection liquid.
Embodiment 14 hydrochloric acid melphalan injection liquids
Take by weighing anhydrous sodium sulfate 2 grams, to 200 milliliters dehydrated alcohol, stir dehydration 100 minutes, filter, dehydrated alcohol must dewater; Take by weighing hydrochloric acid melphalan 2.5 grams, to 95 milliliters of dehydration dehydrated alcohol,, be settled to 100 milliliters of full doses with the dehydration dehydrated alcohol then 25 ℃ of following heated and stirred dissolvings; With the Fructus Mali pumilae acid for adjusting pH value is 4.5; Add 0.2 gram needle-use activated carbon, 25 ℃ adsorbed 30 minutes down; Use filtering with microporous membrane, packing is sealed, and 121 ℃ of sterilizations of high steam 15 minutes promptly get hydrochloric acid melphalan injection liquid.
Embodiment 15 hydrochloric acid melphalan injection liquids
Take by weighing anhydrous sodium sulfate 7 grams, to 200 milliliters dehydrated alcohol, stir dehydration 20 minutes, filter, dehydrated alcohol must dewater; Take by weighing hydrochloric acid melphalan 1.5 grams, to 90 milliliters of dehydration dehydrated alcohol,, be settled to 100 milliliters of full doses with the dehydration dehydrated alcohol then 25 ℃ of following heated and stirred dissolvings; With the Fructus Citri Limoniae acid for adjusting pH value is 3.8; Add 0.7 gram needle-use activated carbon, 45 ℃ adsorbed 30 minutes down; Filter with bag type filter, packing is sealed, and 121 ℃ of sterilizations of high steam 15 minutes promptly get hydrochloric acid melphalan injection liquid.
Embodiment 16 hydrochloric acid melphalan injection liquids
Take by weighing anhydrous sodium sulfate 4 grams, to 200 milliliters dehydrated alcohol, stir dehydration 45 minutes, filter, dehydrated alcohol must dewater; Take by weighing hydrochloric acid melphalan 1.0 grams, to 95 milliliters of dehydration dehydrated alcohol,, be settled to 100 milliliters of full doses with the dehydration dehydrated alcohol then 25 ℃ of following heated and stirred dissolvings; With the Fructus Citri Limoniae acid for adjusting pH value is 4.4; Add 2.0 gram needle-use activated carbons, 25 ℃ adsorbed 60 minutes down; Use filtering with microporous membrane, packing is sealed, and 121 ℃ of sterilizations of high steam 15 minutes promptly get hydrochloric acid melphalan injection liquid.
Embodiment 17 hydrochloric acid melphalan injection liquids
Take by weighing anhydrous sodium sulfate 2 grams, to 200 milliliters dehydrated alcohol, stir dehydration 15 minutes, filter, dehydrated alcohol must dewater; Take by weighing hydrochloric acid melphalan 1.0 grams, to 95 milliliters of dehydration dehydrated alcohol,, be settled to 100 milliliters of full doses with the dehydration dehydrated alcohol then 40 ℃ of following heated and stirred dissolvings; With the Fructus Citri Limoniae acid for adjusting pH value is 5.5; Add 0.6 gram needle-use activated carbon, 35 ℃ adsorbed 30 minutes down; Use filtering with microporous membrane, packing is sealed, and 121 ℃ of sterilizations of high steam 15 minutes promptly get hydrochloric acid melphalan injection liquid.
Embodiment 18 hydrochloric acid melphalan injection liquids
Take by weighing anhydrous calcium chloride 6 grams, to 200 milliliters PEG400, stir dehydration 120 minutes, filter, PEG400 must dewater; Take by weighing hydrochloric acid melphalan 1.0 grams, to 95 milliliters of dehydration PEG400s,, be settled to 100 milliliters of full doses with the dehydration PEG400 then 50 ℃ of following heated and stirred dissolvings; With the Fructus Citri Limoniae acid for adjusting pH value is 3.0; Add 1.5 gram needle-use activated carbons, 40 ℃ adsorbed 30 minutes down; Filter with bag type filter, packing is sealed, and 121 ℃ of sterilizations of high steam 15 minutes promptly get hydrochloric acid melphalan injection liquid.
Embodiment 19 hydrochloric acid melphalan injection liquids
Take by weighing anhydrous sodium sulfate 1 gram, to 200 milliliters dehydrated alcohol, stir dehydration 120 minutes, filter, dehydrated alcohol must dewater; Take by weighing hydrochloric acid melphalan 2.5 grams, to 95 milliliters of dehydration dehydrated alcohol,, be settled to 100 milliliters of full doses with the dehydration dehydrated alcohol then 25 ℃ of following heated and stirred dissolvings; With the Fructus Citri Limoniae acid for adjusting pH value is 5.2; Add 0.5 gram needle-use activated carbon, 25 ℃ adsorbed 40 minutes down; Use filtering with microporous membrane, packing is sealed, and 121 ℃ of sterilizations of high steam 15 minutes promptly get hydrochloric acid melphalan injection liquid.
Embodiment 20 hydrochloric acid melphalan injection liquids
Take by weighing anhydrous sodium sulfate 1.8 grams, to 200 milliliters dehydrated alcohol, stir dehydration 80 minutes, filter, dehydrated alcohol must dewater; Take by weighing hydrochloric acid melphalan 10.0 grams, to 85 milliliters of dehydration dehydrated alcohol,, be settled to 100 milliliters of full doses with the dehydration dehydrated alcohol then 45 ℃ of following heated and stirred dissolvings; With the Fructus Citri Limoniae acid for adjusting pH value is 2.0; Add 1.5 gram needle-use activated carbons, 25 ℃ adsorbed 60 minutes down; Use filtering with microporous membrane, packing is sealed, and 121 ℃ of sterilizations of high steam 15 minutes promptly get hydrochloric acid melphalan injection liquid.
Embodiment 21 hydrochloric acid melphalan injection liquids
Take by weighing anhydrous sodium sulfate 5.0 grams, to 200 milliliters dehydrated alcohol, stir dehydration 60 minutes, filter, dehydrated alcohol must dewater; Take by weighing hydrochloric acid melphalan 7.5 grams, to 80 milliliters of dehydration dehydrated alcohol,, be settled to 100 milliliters of full doses with the dehydration dehydrated alcohol then 50 ℃ of following heated and stirred dissolvings; Regulating pH value with acetic acid is 7.0; Add 0.2 gram needle-use activated carbon, 25 ℃ adsorbed 60 minutes down; Use filtering with microporous membrane, packing is sealed, and 121 ℃ of sterilizations of high steam 15 minutes promptly get hydrochloric acid melphalan injection liquid.
Embodiment 22 hydrochloric acid melphalan injection liquids
Take by weighing anhydrous sodium sulfate 1.0 grams, to 200 milliliters dehydrated alcohol, stir dehydration 90 minutes, filter, dehydrated alcohol must dewater; Take by weighing hydrochloric acid melphalan 7.5 grams, to 80 milliliters of dehydration dehydrated alcohol,, be settled to 100 milliliters of full doses with the dehydration dehydrated alcohol then 50 ℃ of following heated and stirred dissolvings; Regulating pH value with hydrochloric acid is 2.8; Add 1.5 gram needle-use activated carbons, 25 ℃ adsorbed 60 minutes down; Use filtering with microporous membrane, packing is sealed, and 121 ℃ of sterilizations of high steam 15 minutes promptly get hydrochloric acid melphalan injection liquid.
Embodiment 23 hydrochloric acid melphalan injection liquids
Take by weighing anhydrous sodium sulfate 10 grams, to 200 milliliters dehydrated alcohol, stir dehydration 50 minutes, filter, dehydrated alcohol must dewater; Take by weighing hydrochloric acid melphalan 5.0 grams, to 90 milliliters of dehydration dehydrated alcohol,, be settled to 100 milliliters of full doses with the dehydration dehydrated alcohol then 25 ℃ of following heated and stirred dissolvings; Regulating pH value with acetic acid is 3.0; Add 0.5 gram needle-use activated carbon, 25 ℃ adsorbed 60 minutes down; Use filtering with microporous membrane, packing is sealed, and 121 ℃ of sterilizations of high steam 15 minutes promptly get hydrochloric acid melphalan injection liquid.
Embodiment 24 hydrochloric acid melphalan injection liquids
Take by weighing anhydrous sodium sulfate 1 gram, to 200 milliliters dehydrated alcohol, stir dehydration 120 minutes, filter, dehydrated alcohol must dewater; Take by weighing hydrochloric acid melphalan 0.1 gram, to 80 milliliters of dehydration dehydrated alcohol,, be settled to 100 milliliters of full doses with the dehydration dehydrated alcohol then 50 ℃ of following heated and stirred dissolvings; With the Fructus Citri Limoniae acid for adjusting pH value is 4.0; Add 0.1 gram needle-use activated carbon, 25 ℃ adsorbed 60 minutes down; Filter with bag type filter, packing is sealed, and 121 ℃ of sterilizations of high steam 15 minutes promptly get hydrochloric acid melphalan injection liquid.V embodiment 25 hydrochloric acid melphalan injection liquids
Take by weighing anhydrous sodium sulfate 8 grams, to 200 milliliters dehydrated alcohol, stir dehydration 60 minutes, filter, dehydrated alcohol must dewater; Take by weighing hydrochloric acid melphalan 0.2 gram, to 80 milliliters of dehydration dehydrated alcohol,, be settled to 100 milliliters of full doses with the dehydration dehydrated alcohol then 25 ℃ of following heated and stirred dissolvings; Regulating pH value with lactic acid is 5.5; Add 1.5 gram needle-use activated carbons, 25 ℃ adsorbed 60 minutes down; Filter with bag type filter, packing is sealed, and 121 ℃ of sterilizations of high steam 15 minutes promptly get hydrochloric acid melphalan injection liquid.
Embodiment 26 adopts the sterilization stability of the dehydration and the prepared hydrochloric acid melphalan injection liquid of solvent for injection that do not dewater to compare
1. sample preparation
With the prepared hydrochloric acid melphalan injection liquid of the embodiment of the invention 1, as test specimen; Adopt the dehydrated alcohol (water content is about 0.3%) that does not pass through processed as solvent for injection, other preparation process prepares control sample with embodiment 1.
2. sterilising conditions
121 ℃ of sterilizations of high steam 15 minutes.
3. assay method
3.1 chromatographic condition
Adopt high effective liquid chromatography for measuring, mobile phase is: methanol=75/25; The detection wavelength is: 260nm; Column temperature: 25 ℃.
3.2 sample preparation
The accurate respectively sample 0.1ml that draws before and after sterilizing to the 25ml volumetric flask, is settled to scale with dehydrated alcohol, filters, and sample introduction 20 μ l, the record peak area calculates the medicine percentage composition after sterilizing.
4. result
The results are shown in Table 1.
Table 1 adopts the sterilization stability of the dehydration and the prepared hydrochloric acid melphalan injection liquid of solvent for injection that do not dewater to compare
| Sample | Peak area before the sterilization | Peak area before the sterilization | Sterilization back percentage composition |
| Dehydration | ??1726.4 | ??1724.9 | ??99.9％ |
| Not dehydration | ??1718.6 | ??1540.0 | ??89.6％ |
5. conclusion
This evidence, hydrochloric acid melphalan is responsive to moisture content stability, Tuo Shui sample not, sterilization afterwards content has descended about 10%, and impurity peaks obviously increases; And the sample of process processed, medicament contg does not almost change before and after the sterilization, and does not see obvious impurity peaks appearance.This experiment proves that fully hydrochloric acid melphalan of the present invention does not have water injection and improved stability of drug greatly, so dewatering process is an essential characteristics of the present invention, thereby has received the effect of significance.
The comparison of 60 ℃ of accelerated stabilities of embodiment 27 hydrochloric acid melphalan injection liquids of the present invention and hydrochloric acid melphalan freeze-dried powder
1. sample preparation
1.1 test specimen
With the prepared hydrochloric acid melphalan injection liquid of the embodiment of the invention 1, as test specimen.
1.2 the preparation of freeze-dried powder
Take by weighing hydrochloric acid melphalan 0.2 gram, mannitol 10 grams, to 90ml water for injection, ultrasonic 30min, dissolving, and be settled to 100ml, and packing, lyophilizing, gland promptly gets the hydrochloric acid melphalan freeze-dried powder, in contrast sample.
2. investigation condition
Investigate injection of the present invention and freeze-dried powder respectively, the stability under 60 ℃ of acceleration environments.
3. assay method
3.1 chromatographic condition
Adopt high effective liquid chromatography for measuring, mobile phase is: methanol=75/25; The detection wavelength is: 260nm; Column temperature: 25 ℃.
3.2 sample preparation
Respectively at sampling in 5 days, 10 days, precision was got injection 0.1ml, about 0.05 gram of freeze-dried powder respectively, to the 25ml volumetric flask, is settled to scale with dehydrated alcohol respectively, filters sample introduction 20 μ l.Measure content, calculate the medicine percentage composition after sterilizing.
4. result
The results are shown in Table 2.
The comparison of 60 ℃ of accelerated stabilities of table 2 hydrochloric acid melphalan injection liquid of the present invention and hydrochloric acid melphalan freeze-dried powder
| Sample | 5 days medicine percentage compositions | 10 days medicine percentage compositions |
| Injection | ??100.3％ | ??98.5％ |
| Freeze-dried powder | ??20.8％ | ??8.9％ |
5. conclusion
This evidence, hydrochloric acid melphalan injection liquid of the present invention, 60 ℃ of accelerated stabilities are good, and quickening 10 days medicament contgs does not have significant change; And 5 days content of freeze-dried powder acceleration has declined to a great extent to 20.8%, and impurity peaks obviously increases; And when freeze-dried powder redissolved with water for injection, the part medicine can not well dissolve, and needed long-time jolting to dissolve.We know that bound water can't be removed in the lyophilized formulations, promptly so long as lyophilized formulations must have moisture content to exist, also just must cause water sensitivity medicine instability.Hydrochloric acid melphalan injection liquid of the present invention is an anhydrous formulation, has effectively avoided water sensitivity medicine problem of unstable.This experiment has further proved remarkable result of the present invention.
Claims (11)
1. a hydrochloric acid melphalan injection liquid is characterized in that, is made up of hydrochloric acid melphalan, solvent for injection and pH value regulator, and concrete component and consumption are as follows:
Solvent for injection wherein is the anhydrous solvent by obtaining after the processed.
2. a kind of hydrochloric acid melphalan injection liquid according to claim 1 is characterized in that wherein said solvent for injection is selected from dehydrated alcohol, PEG400, propylene glycol, N, the mixture of one or more in the N dimethyl acetylamide.
3. a kind of hydrochloric acid melphalan injection liquid according to claim 1 and 2 is characterized in that, wherein hydrochloric acid melphalan content is the 5-80 mg/ml.
4. a kind of hydrochloric acid melphalan injection liquid according to claim 1 and 2 is characterized in that, wherein said pH value regulator is citric acid, lactic acid, malic acid, hydrochloric acid or acetic acid, regulates pH value to 4-6.
5. the preparation method of a hydrochloric acid melphalan injection liquid as claimed in claim 1 is characterized in that this method is made up of following steps:
Earlier solvent for injection is carried out processed; The hydrochloric acid melphalan that takes by weighing formula ratio then 25-80 ℃ of following heated and stirred dissolving, is settled to full dose with the dehydration solvent for injection to an amount of dehydration solvent for injection; Regulate pH value to 2-7 with the pH value regulator; Adding the bulking value percentage composition is the needle-use activated carbon of 0.01%-2% grams per milliliter, and absorption is 15-120 minute under 25-80 ℃ heating-up temperature; Filtration, packing, seal, sterilize, promptly get hydrochloric acid melphalan injection liquid.
6. the preparation method of hydrochloric acid melphalan injection liquid according to claim 5 is characterized in that, processed wherein is that dehydrant is added in the solvent for injection, stirs dehydration 10-120 minute, filters.
7. the preparation method of hydrochloric acid melphalan injection liquid according to claim 6 is characterized in that, wherein dehydrant is anhydrous sodium sulfate, anhydrous calcium chloride or anhydrous magnesium sulfate, and consumption is the 0.5-15% grams per milliliter.
8. according to the preparation method of claim 5,6 or 7 described hydrochloric acid melphalan injection liquids, it is characterized in that described heated and stirred solution temperature is 25-55 ℃.
9. according to the preparation method of claim 5,6 or 7 described hydrochloric acid melphalan injection liquids, it is characterized in that described needle-use activated carbon consumption is the 0.5-1.5% grams per milliliter, adsorption temp is 25-45 ℃, and adsorption time is 20-40 minute.
10. according to the preparation method of claim 5,6 or 7 described hydrochloric acid melphalan injection liquids, it is characterized in that described filtration is to adopt microporous filter membrane or bag type filter to filter.
11. the preparation method according to claim 5,6 or 7 described hydrochloric acid melphalan injection liquids is characterized in that, described sterilization is to adopt high steam, flowing steam or cross 0.22 μ m microporous filter membrane sterilization.12, the preparation method of hydrochloric acid melphalan injection liquid according to claim 11 is characterized in that, high-temperature steam sterilising temp wherein is 100-121 ℃, and the time is 8-45 minute.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201010198648A CN101856325A (en) | 2010-06-11 | 2010-06-11 | Hydrochloric acid melphalan injection liquid and preparation method thereof |
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| CN201010198648A CN101856325A (en) | 2010-06-11 | 2010-06-11 | Hydrochloric acid melphalan injection liquid and preparation method thereof |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3773498B1 (en) | 2018-03-29 | 2022-06-22 | Project Pharmaceutics GmbH | Liquid pharmaceutical formulation |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101584669A (en) * | 2009-06-19 | 2009-11-25 | 江苏奥赛康药业有限公司 | Melphalan freeze-dried powder injection |
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2010
- 2010-06-11 CN CN201010198648A patent/CN101856325A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101584669A (en) * | 2009-06-19 | 2009-11-25 | 江苏奥赛康药业有限公司 | Melphalan freeze-dried powder injection |
Non-Patent Citations (2)
| Title |
|---|
| 《临床实用药物手册》 20081031 陆凤翔等 盐酸美法仑注射液 江苏科学技术出版社 第152页第5行 1-12 , 第四版 1 * |
| 《国外医学.药学分册》 19860302 诸明 美法仑溶液在制备和贮存中稳定性的研究 103 1-12 , 第2期 2 * |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3773498B1 (en) | 2018-03-29 | 2022-06-22 | Project Pharmaceutics GmbH | Liquid pharmaceutical formulation |
| US11752135B2 (en) | 2018-03-29 | 2023-09-12 | Project Pharmaceutics Gmbh | Liquid pharmaceutical formulation |
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