CN111053745B - Melphalan hydrochloride freeze-dried preparation for injection and preparation method thereof - Google Patents
Melphalan hydrochloride freeze-dried preparation for injection and preparation method thereof Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 34
- OUUYBRCCFUEMLH-YDALLXLXSA-N [(1s)-2-[4-[bis(2-chloroethyl)amino]phenyl]-1-carboxyethyl]azanium;chloride Chemical compound Cl.OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 OUUYBRCCFUEMLH-YDALLXLXSA-N 0.000 title claims abstract description 30
- 229960002514 melphalan hydrochloride Drugs 0.000 title claims abstract description 30
- 238000002347 injection Methods 0.000 title claims abstract description 18
- 239000007924 injection Substances 0.000 title claims abstract description 18
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims abstract description 87
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 54
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- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 description 27
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- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 description 1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
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Abstract
The invention discloses a melphalan hydrochloride freeze-dried preparation for injection, which comprises the following components in parts by mass: 25-30 parts of melphalan hydrochloride, 8-12 parts of povidone, 0.5-0.7 part of citric acid, 4-6 parts of hydrochloric acid and 1000 parts of water for injection. Also provides a preparation method of the melphalan hydrochloride freeze-dried preparation for injection, which remarkably accelerates the redissolution time of the product and reduces the administration risk.
Description
Technical Field
The invention relates to the technical field of medicines, and in particular relates to a hydrochloric acid melphalan freeze-dried preparation for injection.
Background
Melphalan (Melphalan) is an anti-tumor western medicine, has obvious curative effect on multiple myeloma and is also suitable for ovarian cancer. Due to the fact that the redissolution time of the current commercially available product is long, the specific impurities increase quickly in the storage process, and the collapse temperature of the key auxiliary material povidone in the freeze-drying process is low in the low-pH environment, the uniformity of the products in batches and among batches is poor, and certain quality risks exist.
The active pharmaceutical ingredient melphalan hydrochloride of the product is easy to form insoluble crystals or microcrystals when freeze-dried in all solvent systems, so that the product is dissolved in a matched diluent for a long time, or even the freeze-dried powder cake is incompletely redissolved if the diluent is not added rapidly according to the instruction and shaken vigorously, and the risk of insufficient administration dosage is caused. Meanwhile, the stability time of the product is short, intravenous infusion administration needs to be completed within 1 hour after reconstitution is completed, the longer reconstitution time shortens the administration time, and the faster administration of the active pharmaceutical ingredients may cause more serious side effects to patients.
Only 1 American company obtains imported drug registration batches of hydrochloric acid melphalan freeze-dried powder injection for injection at present, and no company obtains production batches at home.
Castillo etc. developed a new formulation and applied for US patent US 20130131174a1, one of the main objectives of which is "to solve the problem of the original ground product dissolving very slowly, sometimes not completely". Compared with the original ground product, the prescription uses glacial acetic acid or other buffer salts to replace povidone which is a key auxiliary material for freeze-drying the active pharmaceutical ingredient bottle, and the freeze-drying bottle is directly re-dissolved to pH 5-6 by using physiological saline or an aqueous solution of buffer salts with pH 5-6. However, for the variety, the active pharmaceutical ingredient is easy to form crystals in the freeze-drying process, and the crystal lattice energy of the active pharmaceutical ingredient is larger, so that the remarkable redissolution difficulty is caused, while the povidone can inhibit the active pharmaceutical ingredient from forming crystals in the freeze-drying process and is used for enhancing and dissolving the active pharmaceutical ingredient and auxiliary materials in a solvent system matched with a diluent, so that the preparation formula developed by the patent is difficult to inhibit the active pharmaceutical ingredient from forming crystals, and the problem of large difference between the appearance and the redissolution time of the freeze-dried product in batches and between batches due to the crystallization or microcrystal of the active pharmaceutical ingredient in the variety is solved. And there are a lot of documents and patents describing that the solubility of the active pharmaceutical ingredient in an aqueous solution is extremely low in the range of pH 1.8 to 7.0, and a large proportion of an organic solvent must be used to enhance the solubility, and thus the utility of the patent is poor.
James.d. pipkin etc. developed a new formulation and applied for US patent US20140213650a1 (chinese patent CN201080033495.8), which compared to the original research product, changed the key excipients povidone to sulfobutyl-beta cyclodextrin and changed the ratio of the original excipients from 55.98: the 20 (w/w) was greatly increased to 55.98: 2700(w/w), Melphalan hydrochloride molecules are embedded into the cyclodextrin rings using sulfobutyl- β cyclodextrin. Since the ratio of melphalan hydrochloride molecular weight to cyclodextrin molecular weight is 341.66: 2163, i.e., the formulation uses about 8 times the ratio of cyclodextrin to include the API molecules, excess inclusion is used because the API still faces dissolution problems during production. Meanwhile, the compound is extruded or damaged to some extent in the freeze-drying process of the prescription, and the inclusion needs to be formed again in the re-dissolving process, so that the problem of incomplete re-dissolving of the pressed powder is solved, but the re-dissolving time is still long. The product has short stability time after reconstitution, and the stability time after reconstitution is only 1 hour, so that the drug administration needs to be completed quickly, the long reconstitution time causes a large risk of solution stability on one hand, the long reconstitution time shortens the drug administration time on the other hand, and the faster drug administration of the active drug ingredients may cause serious side effects of patients. According to the vascular irritation experiment of the rabbit variety in the invention, when a dosage ramp experiment of 1.5 times of administration dosage is carried out, 20% of rabbits die during administration, abnormal phenomena such as yellow brown, spleen congestion, gastrointestinal tract flatulence and the like are found after the rabbit variety is dissected, a serious drug toxicity reaction is shown, and the safety window of the rabbit variety is smaller and the toxic and side effects are stronger. Meanwhile, beta cyclodextrin has strong nephrotoxicity, and the safety risk of the auxiliary material is increased by rapid administration, so that the auxiliary material has double risks of safety.
On the other hand, during the long-term storage of the product, the melphalan molecule (formula 1) is easy to form a certain specific dimer impurity (formula 2), the impurities are formed by nucleophilic reaction of one chloroethyl group of active medicine ingredient molecules and another free acid-based oxygen, the reaction is SN2 reaction, which is more easily induced to occur in a slightly alkaline solid microenvironment, so that for all the commercial melphalan drugs on the market, in the preparation process, although a large proportion of hydrochloric acid is added for salifying melphalan and promoting the melphalan to be dissolved under the condition of low pH, however, the hydrochloric acid molecules are removed together with the water molecules in the freeze-drying process, so that the freeze-dried finished product cannot maintain a slightly acidic solid microenvironment, and therefore, in the storage process of the freeze-dried product, the dimer impurity is significantly increased and is not easily degraded during reconstitution and administration, which may cause the risk of impurity-induced genotoxicity and insufficient administration dosage.
Formula 1: melphalan hydrochloride structural formula 2: structural formula of melphalan dimer
Disclosure of Invention
In order to solve the technical problems, the invention provides a melphalan hydrochloride freeze-dried preparation for injection, which can obviously inhibit melphalan from forming insoluble crystals or microcrystals, obviously quickens the redissolution time of a product and reduces the administration risk. Meanwhile, compared with the original ground product, the freeze-dried product of the invention obviously reduces the growth rate of impurities such as melphalan dimer and the like in the storage process, thereby reducing the genotoxicity risk of related impurity administration and the risk of insufficient administration dosage of active pharmaceutical ingredients close to the effective period caused by fast impurity growth.
In order to realize the purpose of the invention, the invention adopts the technical scheme that:
a freeze-dried preparation of melphalan hydrochloride for injection comprises the following components in parts by mass: 25-30 parts of melphalan hydrochloride, 8-12 parts of povidone, 0.5-0.7 part of citric acid, 4-6 parts of hydrochloric acid and water for injection to reach the constant volume of 1000 parts.
According to the invention, citric acid is added in the formula, and after hydrochloric acid molecules are extracted in the freeze-drying process, the citric acid adjusts the API microenvironment of the freeze-dried cake, inhibits the formation of dimers in the long-term standing process of the freeze-dried cake, and solves the problems of impurity increase and content reduction.
The citric acid has higher melting point and stronger hydroxyl polarity, and can form stronger hydrogen bonds with melphalan hydrochloride and povidone molecules, so that no content loss is caused in the freeze-drying process, the API microenvironment of the freeze-dried powder cake is adjusted, and the solid system of the raw material medicine keeps acidity. Citric acid is limited to 0.5-0.7 part as the optimal addition amount, so that the API microenvironment of the freeze-dried powder cake can be just adjusted, and the purposes of inhibiting the freeze-dried powder cake from forming dimers in the long-term standing process and inhibiting melphalan from forming insoluble crystals or microcrystals are achieved; if the addition amount of citric acid is excessive, the product prescription can be obviously changed, the condition of FDA Q1 and Q2 bioequivalence requirements is not met, the safety evaluation of the product and the pharmacodynamics clinical test need to be carried out again, and meanwhile, if the addition amount of auxiliary materials is excessive, the absorption of the pharmaceutical ingredients can be interfered, the clinical pharmacodynamics is obviously changed, the curative effect of the product cannot meet the clinical requirement, and therefore, the addition amount of the citric acid is limited to 0.5-0.7 part.
The invention also provides a preparation method of the melphalan hydrochloride freeze-dried preparation for injection, which comprises the following steps:
A. adding 70-80% of the prescription amount of water for injection into the liquid preparation tank;
B. adding hydrochloric acid in a prescription amount, then adding melphalan in a prescription amount, quickly stirring until the hydrochloric acid and the melphalan are completely dissolved, and immediately reducing the temperature of the liquid medicine to 2-6 ℃ so as to remarkably improve the stability of the liquid medicine, reduce the generation rate of product impurities and reduce the safety risk of administration;
C. stirring and adding citric acid with the amount of the prescription, slowly stirring until the mixture is clear, adding povidone with the amount of the prescription, and slowly stirring until a uniform clear transparent solution is formed;
D. adding the rest prescription amount of water for injection to constant volume, sterilizing, filtering, and bottling to obtain the preparation product.
The step A of the invention keeps the temperature at 13-18 ℃, and under the temperature condition, the solution has more proper dissolution time and better impurity control level.
The hydrochloric acid is 0.5mol/L hydrochloric acid solution.
In the step B, the rotation speed of rapid stirring is 340-360rmp, and in the step C, the rotation speed of slow stirring is 120-140 rpm. The purpose of rapid stirring is to accelerate dissolution, and the purpose of slow stirring is to: the intermolecular bonding force strength such as hydrogen bond, dispersion force, van der waals force and the like is weaker, the shearing force formed at a slower rotating speed is weaker, the balance of the intermolecular bonding force of citric acid, povidone and raw material medicine molecules is favorably maintained, the freeze-dried product is favorably kept in a solid structure of a bonding state in a pre-freezing stage, and the collapse temperature of the product is improved.
The invention has the beneficial effects that:
1. according to the invention, under the condition of meeting the biological equivalence requirements of FDA Q1 and Q2, 0.5-0.7 part of citric acid is added in the prescription, after hydrochloric acid molecules are extracted in the freeze-drying process, the citric acid adjusts the API microenvironment of the freeze-dried powder cake, inhibits the freeze-dried powder cake from forming a dimer in the long-term standing process, and inhibits melphalan from forming insoluble crystals or microcrystal impurities from increasing, so that the problem of melphalan content reduction is solved, and compared with the original ground product and the commercial product, the related impurity level and safety risk of the product are reduced, and the effectiveness is improved.
2. According to the invention, by adjusting the formula of the product and adjusting the feeding sequence, a specific bonding mode and bonding force are formed in the solution, the formation of insoluble crystals or microcrystals of melphalan can be obviously inhibited, the redissolution time of the product is obviously accelerated, and the administration risk is reduced; meanwhile, the collapse temperature of the freeze-dried pressed powder is obviously improved, the uniformity of products in batches and among batches is improved, and the quality risk of the products is reduced.
Drawings
FIG. 1 is a graph of the rheological viscosity versus different addition sequences.
Detailed Description
In order to more clearly and specifically illustrate the technical solution of the present invention, the present invention is further described by the following embodiments. The following examples are intended to illustrate the practice of the present invention and are not intended to limit the scope of the invention.
Example 1
A freeze-dried preparation of melphalan hydrochloride for injection is characterized by comprising the following components in parts by mass: 25 parts of melphalan hydrochloride, 8 parts of povidone, 0.5 part of citric acid, 4 parts of hydrochloric acid and water for injection, wherein the volume is up to 1000 parts.
Example 2
A freeze-dried preparation of melphalan hydrochloride for injection is characterized by comprising the following components in parts by mass: 30 parts of melphalan hydrochloride, 12 parts of povidone, 0.7 part of citric acid, 6 parts of hydrochloric acid and water for injection, and the volume is fixed to 1000 parts.
Example 3
A freeze-dried preparation of melphalan hydrochloride for injection is characterized by comprising the following components in parts by mass: 28 parts of melphalan hydrochloride, 10 parts of povidone, 0.6 part of citric acid, 4.8 parts of hydrochloric acid and water for injection until the volume is 1000 parts.
Example 4
A freeze-dried preparation of melphalan hydrochloride for injection is characterized by comprising the following components in parts by mass: 26 parts of melphalan hydrochloride, 9 parts of povidone, 0.55 part of citric acid, 4.5 parts of hydrochloric acid and water for injection until the volume is 1000 parts.
Example 5
A freeze-dried preparation of melphalan hydrochloride for injection is characterized by comprising the following components in parts by mass: 29 parts of melphalan hydrochloride, 10 parts of povidone, 0.65 part of citric acid, 5 parts of hydrochloric acid and water for injection to reach the volume of 1000 parts.
According to the invention, through the experimental accidental discovery, different feeding sequences, different temperatures when raw and auxiliary materials are added and the sequence of the cooling step can have obvious influence on the solid environment of the freeze-dried powder cake, so that the collapse temperature of the powder cake in the freeze-drying process is influenced, and the uniformity and the stability of the freeze-dried finished product in batches and among batches are influenced.
In order to research whether relevant factors have obvious influence on the quality attribute of a product, the invention carries out the following experiments to confirm whether different bond combination modes can influence the solution property, the invention generates samples of different hydrogen bond combination modes according to different feeding sequences, whether citric acid and other factors under the same experiment condition, the generated solution uses a rheometer to represent the rheological property, such as rheological viscosity, nonlinear shear stress hedging and the like, uses a tuning differential scanning calorimeter to represent the thermal effect of a solution system, uses a densitometer to represent the density change, uses a freeze-drying microscope to confirm the collapse temperature change and the like, and partial research results are as follows:
table 1: contrast of collapse temperature and rheological viscosity for different liquid medicine prescriptions and feeding sequences
As can be seen from the above table and fig. 1, under the same conditions, the collapse temperature and the rheological viscosity of the liquid medicines prepared by different prescriptions and charging sequences are significantly changed, the collapse temperature after citric acid is added is significantly increased, and the rheological viscosity is also significantly changed, especially after the charging sequence 3 is adopted. The possible reason is that the bonding force and the bonding quantity of hydrogen bonds formed by citric acid and povidone and bulk drugs are different after the citric acid is added, so that molecules of povidone are in different entwisted states of relaxation or curling, and the solution properties are different. In addition, the detection of rheological viscosity, nonlinear shear stress hedging, density, collapse temperature and the like are carried out on the liquid medicines with different prescriptions and different charging sequences, and the indexes are found to be different. The experiments prove that the key combination mode and the number of different prescriptions and different feeding modes of the same prescription can influence the solution characteristics, thereby influencing the product properties. The method has the advantages that a specific bonding mode and bonding force are formed in the solution by adjusting the feeding sequence, so that the formation of insoluble crystals or microcrystals of melphalan can be inhibited, the redissolution time of the product is shortened, the administration risk is reduced, the collapse temperature of the freeze-dried cake powder can be increased, the uniformity of the product in batches and among batches is improved, and the quality risk of the product is reduced.
Example 6
This example is a method of making example 3, comprising the steps of:
A. adding 70% of the prescription dose of water for injection into the liquid preparation tank, and keeping the temperature at 13 ℃;
B. adding hydrochloric acid with the prescription amount, then adding melphalan bulk drug with the prescription amount, rapidly stirring until the melphalan bulk drug is completely dissolved, and immediately cooling the liquid medicine to 2 ℃;
C. stirring and adding citric acid with the amount of the prescription, slowly stirring until the mixture is clear, adding povidone with the amount of the prescription, and slowly stirring until a uniform clear transparent solution is formed;
D. adding the rest prescription amount of water for injection to constant volume, sterilizing, filtering, and bottling to obtain the preparation product.
In the step B, the rotating speed of rapid stirring is 340rmp, and in the step C, the rotating speed of slow stirring is 120 rpm.
Example 7
This example is a method of making example 4, comprising the steps of:
A. adding 80% of the prescription dose of water for injection into the liquid preparation tank, and keeping the temperature at 18 ℃;
B. adding hydrochloric acid with the prescription amount, then adding melphalan bulk drug with the prescription amount, rapidly stirring until the melphalan bulk drug is completely dissolved, and immediately cooling the liquid medicine to 6 ℃;
C. stirring and adding citric acid with the amount of the prescription, slowly stirring until the mixture is clear, adding povidone with the amount of the prescription, and slowly stirring until a uniform clear transparent solution is formed;
D. adding the rest prescription amount of water for injection to constant volume, sterilizing, filtering, and bottling to obtain the preparation product.
In the step B, the rotating speed of rapid stirring is 360rmp, and in the step C, the rotating speed of slow stirring is 140 rpm.
Example 8
This example is a method of making example 5, comprising the steps of:
A. adding 75% of the prescription dose of water for injection into the liquid preparation tank, and keeping the temperature at 15 ℃;
B. adding hydrochloric acid with the prescription amount, then adding melphalan bulk drug with the prescription amount, rapidly stirring until the melphalan bulk drug is completely dissolved, and immediately cooling the liquid medicine to 3 ℃;
C. stirring and adding citric acid with the amount of the prescription, slowly stirring until the mixture is clear, adding povidone with the amount of the prescription, and slowly stirring until a uniform clear transparent solution is formed;
D. adding the rest prescription amount of water for injection to constant volume, sterilizing, filtering, and bottling to obtain the preparation product.
The hydrochloric acid is 0.5N hydrochloric acid solution.
In the step B, the rotating speed of rapid stirring is 350rmp, and in the step C, the rotating speed of slow stirring is 130 rpm.
Example 9
About 7L of water for injection is added into the liquid preparation tank, and the temperature is kept between 13 and 18 ℃ by using a low-temperature control system. 2390g of a pre-prepared 0.5N hydrochloric acid solution was added. 279.9 g of melphalan hydrochloride bulk drug is added and stirred rapidly until a homogeneous clear solution is formed. And reducing the temperature of the liquid medicine to 2-6 ℃. Citric acid (6.2 g) was added and stirred slowly until a homogeneous clear solution was formed. 100g of povidone K12 was added and stirred slowly until a homogeneous clear solution formed. The volume of the liquid medicine is adjusted to 10kg by using water for injection. The liquid medicine is sterilized and filtered by two sterilizing filters connected in series. Washing the filter and the filling system with the liquid medicine for 2 times before filling, and filling 2.0 mL of liquid medicine into a 15 mL neutral borosilicate transparent bottle.
The freeze-drying process of the invention is as follows:
a. feeding: a freeze dryer for feeding the materials to a plate layer temperature of 0-5 ℃;
b. freezing: pre-freezing the product for 40min in a freeze drying chamber at 0-5 ℃;
cooling to minus 50 to minus 40 ℃ within 2 to 3 hours, and pre-freezing the product for 4 to 6 hours;
heating to-17-25 ℃ within 2-5 h, and pre-freezing the product for 3-6 h;
cooling to minus 50 to minus 40 ℃ within 2 to 3 hours, and pre-freezing the product for 5 to 8 hours;
c. sublimation drying: keeping the temperature at minus 50 to minus 30 ℃ and 25 mu bar for 80 to 100 hours;
heating to-10-0 ℃ within 5h, keeping the temperature at 30 mu bar for 3 h;
d. desorption and drying: heating to 10-20 ℃ within 2-3 h, keeping at 60 mu bar for 3 h;
heating to 30-40 ℃ within 2-3 h, keeping at 60 mu bar for 6 h;
heating to 40-50 ℃ within 45min, keeping at 60 mu bar for 5 h;
cooling to 20-30 ℃ within 10min, keeping at 60 μ bar for 30 min;
according to the stability analysis results of finished products in different freeze-drying periods, the stability of the finished products is improved to a certain extent after annealing is carried out at the temperature of more than the glass transition temperature (Tg) of the povidone solution, namely more than-25 ℃. The reason for this is that the amorphous polymer is not in a thermodynamic equilibrium state in the vicinity of Tg, and its structure is a random coil-like amorphous state in which entanglement is restricted, and when an annealing stage is performed, a molecular segment having a considerable amount of polymer is disentangled by energy, so that its internal stereoregularity is changed, and an isotactic or syndiotactic polymer molecular segment having a regular structure is locally formed after rearrangement. Meanwhile, the internal structure is recombined and reassembled after annealing treatment, so that the crystalline stereocomplex citric acid generates ordered flow in the space barrier, a trap of free volume caused by interaction between polymer entanglement and chains in a system is filled, the free volume is reduced, the distribution condition of the citric acid in the solid pressed powder is adjusted, the solid microenvironment of API molecules is improved, the stability of a finished product is improved to a certain extent, the freeze-drying period is optimized, the melphalan can be further inhibited from forming insoluble crystals or microcrystals, the redissolution time of the product is accelerated, and the administration risk is reduced.
The invention compares the re-dissolving time and stability of the prepared finished product with the original product, and the details are shown in tables 2-4.
TABLE 2 comprehensive comparison of the present invention's home-made sample with the original ground sample
TABLE 3 stability testing of products under accelerated conditions
Table 4 stability testing of products under long term conditions
As can be seen from table 2, compared with the original ground product, the melphalan freeze-dried preparation of the present invention significantly accelerates the reconstitution time, reduces the administration risk, has lower impurity content than the original ground product, reduces the related impurity level and safety risk of the product, and improves the effectiveness. As can be seen from tables 3 and 4, compared with the original research products, the product of the invention has the advantages that the impurities increase more slowly with time in the storage process, and the increase speed of the impurities such as melphalan dimer is obviously reduced, so that the risk of genotoxicity of related impurity administration and the risk of insufficient administration dosage of the active pharmaceutical ingredient close to the effective period caused by fast increase of the impurities are reduced.
The above-mentioned embodiments only express the specific embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the present invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention.
Claims (3)
1. The preparation method of the melphalan hydrochloride freeze-dried preparation for injection is characterized in that the raw materials consist of the following components in percentage by mass: 25-30 parts of melphalan hydrochloride, 8-12 parts of povidone, 0.5-0.7 part of citric acid, 4-6 parts of hydrochloric acid and water for injection to reach the constant volume of 1000 parts;
the method comprises the following steps:
A. adding 70-80% of the prescription amount of water for injection into the liquid preparation tank;
B. adding hydrochloric acid with a prescription amount, then adding the melphalan hydrochloride raw material medicine with the prescription amount, quickly stirring until the raw material medicine is completely dissolved, and immediately cooling the liquid medicine to 2-6 ℃;
C. stirring and adding citric acid with the amount of the prescription, slowly stirring until the mixture is clear, adding povidone with the amount of the prescription, and slowly stirring until a uniform clear transparent solution is formed;
D. adding the rest prescription amount of water for injection to constant volume, sterilizing, filtering, filling, and lyophilizing to obtain preparation product;
the step B, the fast stirring speed is 340-360rmp, and the step C, the slow stirring speed is 120-140 rpm.
2. The method for preparing a lyophilized formulation of melphalan hydrochloride for injection according to claim 1, wherein the temperature of step a is maintained at 13-18 ℃.
3. The method for preparing the lyophilized preparation of melphalan hydrochloride for injection according to claim 1, wherein the hydrochloric acid is 0.5mol/L hydrochloric acid solution.
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