CN114557968A - Composition containing freeze-dried preparation and redissolving solvent, preparation method and application - Google Patents
Composition containing freeze-dried preparation and redissolving solvent, preparation method and application Download PDFInfo
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Abstract
The invention discloses a composition containing a freeze-dried preparation and a redissolving solvent, a preparation method and application. The invention provides aA formulation combination comprising: the freeze-dried preparation containing the compound 1 serving as an inhibitor of Bcl-2/Bcl-xL or pharmaceutically acceptable salt thereof and a proper excipient is combined with a redissolving solvent composition, and the preparation is suitable for clinical injection administration and has the advantages of good stability, good redissolving effect and the like.
Description
Technical Field
The invention relates to a composition containing a freeze-dried preparation and a redissolving solvent, a preparation method and application.
Background
The compound (3R) -1- (3- (4- (4- (4- (3- (2- (4-chlorophenyl) -1-isopropyl-4-methanesulfonyl-5-methyl-1H-pyrrol-3-yl) -5-fluorophenyl) piperazin-1-yl) -phenylamino sulfonyl) -2-trifluoromethanesulfonyl-anilino) -4-thiophenyl-butyl) -piperidine-4-carboxylic acid 3-phosphonopropyl ester (hereinafter referred to as compound 1) or a pharmaceutically acceptable salt thereof is a sulfonamide that is a Bcl-2/Bcl-xL inhibitor of the formula:
compound 1 or a pharmaceutically acceptable salt thereof is a potential Bcl-2 and/or Bcl-xL inhibitor (see WO 2014113413). The compound can effectively induce apoptosis of cancer cells, has action mechanism highly consistent with that of targeting Bcl-2 and Bcl-xL, and can treat various cancers. We currently performed two phase I dose escalation trials of this compound in the united states and australia on patients with advanced cancer. One phase I dose escalation/extension trial (as monotherapy) was performed concurrently on SCLC patients in china.
However, the compound 1 is extremely poor in solubility in an acidic or near-neutral solution, the solubility is greatly improved under alkaline conditions, but the compound is unstable under alkaline conditions, and the process for exploring an injection preparation formula capable of being industrialized has high challenge.
Disclosure of Invention
The invention provides a stable composition containing a compound 1 or pharmaceutically acceptable salt thereof, a freeze-dried preparation and a re-dissolving solvent (vehicle), and a preparation method and application thereof. The preparation combination comprises the compound 1 or the freeze-dried powder of the pharmaceutically acceptable salt thereof and a redissolution solvent, the freeze-dried powder injection has good stability, the screened redissolution solvent prescription can redissolve the freeze-dried powder, the requirements of the injection such as pH, clarity, osmotic pressure and the like can be met after redissolution, the clinical redissolution effect is good, and the preparation combination is suitable for clinical application. Compound 1 has the structure shown below:
the present invention provides a formulation combination comprising: a lyophilized formulation and a reconstituted solvent composition;
the freeze-dried preparation is prepared by freeze-drying a freeze-dried solution comprising the following raw material components according to a conventional freeze-drying method in the field: compound 1 or a pharmaceutically acceptable salt thereof, a lyophilized scaffold material, a co-solvent (co-solvent), water, and optionally may further comprise a pH adjusting agent;
the redissolving solvent composition comprises the following components in percentage by mass and volume (w/v): 10-15% of polyethylene glycol, 3-10% of surfactant, 2-20% of monohydric alcohol containing 1-4 carbon atoms, pH regulator and water, wherein the pH of the redissolution solvent is 9-12.
In one embodiment of the present invention, in the raw material components of the lyophilized preparation, the lyophilized framework material (also referred to as proppant, scaffold or lyoprotectant) may be a lyophilized framework material conventional in the art, such as: one or more of glucose, sucrose, xylitol, sorbitol, mannitol, dextran, polyethylene glycol, lactose, raffinose, arginine, glycine, histidine, and trehalose; preferably trehalose, more preferably α, α -trehalose.
In one embodiment of the present invention, in the raw material components of the lyophilized preparation, the co-solvent may be a monohydric alcohol containing 1 to 4 carbon atoms, such as one or more of methanol, ethanol, propanol and tert-butanol; tert-butanol is preferred.
In a certain embodiment of the present invention, in the raw material components of the lyophilized preparation, the water is deionized water, purified water, water for injection or sterilized water for injection; such as water for injection or sterile water for injection.
In one embodiment of the present invention, in the raw material components of the lyophilized preparation, the pH adjusting agent may be selected from the group consisting of: hydroxide, phosphate, dihydrogen phosphate, citrate, tartrate, arginine, carbonate, bicarbonate, acetate, meglumine, borate, Tris and HCl; for example selected from the group consisting of: sodium hydroxide, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium hydroxide, sodium citrate, sodium carbonate, potassium carbonate, lithium carbonate, sodium bicarbonate, sodium acetate and HCl; for example NaOH and/or HCl, for example 10N NaOH and/or 5N HCl.
In a certain scheme of the invention, in the raw material components of the freeze-dried preparation, the mass parts of the freeze-dried framework material are as follows, wherein the mass parts of the compound 1 are as follows: for example, it is 4 to 20 parts, preferably 10 to 20 parts, and more preferably 16 parts.
In a certain embodiment of the present invention, in the raw material components of the lyophilized preparation, based on 1 part of compound 1, the mass parts of the cosolvent may be the mass parts conventional in the lyophilized preparations in the art, for example: 60 to 120 parts, preferably 80 to 100 parts, and more preferably 90 to 92 parts (e.g., 91.5 parts).
In a certain embodiment of the present invention, in the raw material components of the lyophilized preparation, based on 1 part of compound 1, the parts by weight of water may be the parts by weight conventionally used in such lyophilized preparations in the art, for example: 60 to 120 parts, preferably 80 to 100 parts, and more preferably 90 to 92 parts (e.g., 91.5 parts).
Preferably, the freeze-dried preparation is obtained by freeze-drying a freeze-dried solution containing the following raw material components in parts by mass according to a freeze-drying method conventional in the art: 1 part of compound 1, 4-20 parts of freeze-dried skeleton material, 60-120 parts of cosolvent (cosolvent) and 60-120 parts of water, and optionally a proper amount of pH regulator.
Preferably, the freeze-dried preparation is obtained by freeze-drying a freeze-dried solution containing the following raw material components in parts by mass according to a freeze-drying method conventional in the art: 1 part of compound 1, 10-20 parts of freeze-dried skeleton material, 80-100 parts of cosolvent (cosolvent) and 80-100 parts of water, and optionally a proper amount of pH regulator.
Preferably, the freeze-dried preparation is obtained by freeze-drying a freeze-dried solution containing the following raw material components in parts by mass according to a freeze-drying method conventional in the art: 1 part of compound 1, 16 parts of freeze-dried skeleton material, 90-92 parts of cosolvent (cosolvent) and 90-92 parts of water, and optionally a proper amount of pH regulator.
In a certain scheme of the invention, the freeze-dried preparation is obtained by freeze-drying a freeze-dried solution containing the following raw material components in parts by mass according to a conventional freeze-drying method in the field: 1 part of compound 1, 16 parts of alpha, alpha-trehalose, 91.5 parts of tert-butyl alcohol, 91.5 parts of water and a proper amount of pH regulator.
In one embodiment of the present invention, in the reconstituted solvent composition, the polyethylene glycol is selected from polyethylene glycol PEG200-PEG1000, such as one or more of polyethylene glycol PEG200, PEG300, PEG400 and PEG600, and further such as PEG 400.
In one embodiment of the present invention, the solvent composition is a solvent compositionThe surfactant is a nonionic surfactant selected from the group consisting of: hydroxystearic acid and polyvinyl alcohol copolymers and the like (e.g., 12-hydroxystearic acid-polyvinyl alcohol copolymer and the like), polymers of hydroxystearic acid and α -hydro- Ω -hydroxypoly (oxy-1, 2-ethanediyl) and the like (e.g., polymers of 12-hydroxystearic acid and α -hydro- Ω -hydroxypoly (oxy-1, 2-ethanediyl) and the like), polyethylene glycol-15 hydroxystearate and the like (e.g., polyethylene glycol-15 hydroxystearate)
And analogs thereof), cholic acid, sodium cholate, a tween (e.g., one or more of tween 20, tween 60, and tween 80), a span (e.g., one or more of span 20, span 60, and span 65), a poloxamer, and a castor oil polyoxyl ester; such as Tween 80,
And one or more of castor oil polyoxyl ester (35) (or ELP or polyoxyl 35 castor oil), also for example
HS-15 (HS-15 for short).
In one embodiment of the present invention, in the redissolving solvent composition, the monohydric alcohol containing 1 to 4 carbon atoms is one or more of methanol, ethanol, propanol and tert-butanol; such as (anhydrous) ethanol and/or propanol.
In one embodiment of the present invention, in the reconstituted solvent composition, the pH adjusting agent is selected from the group consisting of: hydroxides, phosphates, dihydrogen phosphates, citrates, carbonates, hydrogen carbonates and acetates; for example selected from the group consisting of: sodium hydroxide, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium hydroxide, sodium citrate, sodium carbonate, potassium carbonate, lithium carbonate, sodium bicarbonate, and sodium acetate; such as sodium carbonate and/or sodium bicarbonate.
In one embodiment of the present invention, in the reconstituted solvent composition, the water is deionized water, purified water, water for injection or sterilized water for injection; such as water for injection or sterile water for injection.
In one embodiment of the invention, the reconstituted solvent composition comprises 10% to 15% (w/v) polyethylene glycol, preferably 11% to 13% (w/v) polyethylene glycol.
In one embodiment of the invention, the reconstituted solvent composition comprises 3% to 10% (w/v) surfactant, preferably 4% to 8% (w/v) surfactant.
In one embodiment of the invention, the reconstituted solvent composition comprises 2% to 20% (w/v) monohydric alcohol of 1 to 4 carbon atoms, preferably 3% to 10% (w/v) monohydric alcohol of 1 to 4 carbon atoms; further preferably 3% to 8% (w/v) of a monohydric alcohol having 1 to 4 carbon atoms; more preferably 3% to 6% (w/v) of a monohydric alcohol containing 1 to 4 carbon atoms or 4% to 8% (w/v) of a monohydric alcohol containing 1 to 4 carbon atoms.
In one embodiment of the present invention, the reconstitution solvent composition includes a suitable amount of a pH adjusting agent, and the pH of the reconstitution solvent composition is 9-12, preferably 10-12, and more preferably 11-12.
In one embodiment of the present invention, when the pH adjuster is carbonate in the reconstituted solvent composition, the content of the pH adjuster is 0.10 to 0.15% (w/v), preferably 0.12% (w/v) by mass volume.
In one embodiment of the present invention, the redissolving solvent composition comprises the following components in percentage by mass (w/v): 10-15% of polyethylene glycol, 3-10% of surfactant, 2-8% of monohydric alcohol containing 1-4 carbon atoms, pH regulator and water, wherein the pH value of the redissolution solvent is 10-12.
In one embodiment of the present invention, the redissolving solvent composition comprises the following components in percentage by mass (w/v): 11-13% of polyethylene glycol, 4-8% of surfactant, 3-6% of monohydric alcohol containing 1-4 carbon atoms, pH regulator and water, wherein the pH value of the redissolution solvent composition is 11-12;
in one embodiment of the present invention, the redissolving solvent composition comprises the following components in percentage by mass (w/v): 11% -13% of polyethylene glycol, 4% -8% of surfactant, 4% -8% of monohydric alcohol containing 1-4 carbon atoms, pH regulator and water, wherein the pH value of the redissolution solvent composition is 9-10.
In one embodiment of the present invention, when the pH regulator in the redissolving solvent composition is carbonate, the concentration is 10 to 13mmol/L, preferably 11 to 13 mmol/L.
In one embodiment of the present invention, when the pH regulator in the reconstituted solvent composition is bicarbonate, the concentration is 60-70mmol/L, preferably 65-70 mmol/L.
In one embodiment of the present invention, the redissolving solvent composition comprises the following components by mass volume percentage (w/v): 11% of polyethylene glycol 400, 8% of Solutol HS-15, 6% of absolute ethyl alcohol, 0.12% of sodium carbonate and the balance of water for injection.
In one embodiment of the present invention, the mass-to-volume ratio of the compound 1 to the reconstitution solvent composition during reconstitution may be 20mg/mL or less; for example, 18mg/mL, 16mg/mL, 10mg/mL, 8mg/mL, 6 mg/mL.
In one aspect of the present invention, the redissolving solvent composition is prepared by a preparation method comprising the following steps:
weighing the components according to the redissolving solvent composition in any one of the above schemes;
and uniformly mixing the polyethylene glycol, the surfactant, the monohydric alcohol containing 1-4 carbon atoms and part of water, adding the pH regulator, dissolving, adding the rest water to a constant volume, and uniformly mixing to obtain the redissolving solvent composition.
In a certain aspect of the present invention, wherein the lyophilized preparation is prepared by a preparation method comprising the following steps:
weighing the raw material components of the freeze-dried preparation according to any one scheme;
(1) mixing the cosolvent with the compound 1 and the freeze-dried framework material to obtain a mixed solution 1;
(2) mixing the mixed solution 1 with water and a proper amount of pH regulator, and filtering to obtain a solution 2;
(3) filling, freezing and drying to obtain the freeze-dried preparation.
The invention provides a redissolving solvent composition for redissolving a freeze-dried preparation, wherein the redissolving solvent composition can be the redissolving solvent composition in any scheme of the preparation combination.
The invention provides a freeze-dried preparation of compound 1, which can be the freeze-dried preparation in any one of the above preparation combinations. The present invention also provides a kit comprising: one pharmaceutical container containing the lyophilized formulation and the other pharmaceutical container containing the reconstituted solvent composition; the lyophilized formulation and the reconstituted solvent composition are defined as in any one of the above-described formulation combinations.
The pharmaceutical container of the present invention may be an amber or colorless glass vial with a resilient stopper and a crimped aluminum cap or any amber or colorless container suitable for use in a point-of-use system. The medicinal container in the invention includes but is not limited to ampoule or penicillin bottle, preferably penicillin bottle.
"q.s.", "a.q." as used herein means "an amount appropriate".
The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.
The reagents and starting materials used in the present invention are commercially available.
The positive progress effects of the invention are as follows: the preparation combination, the composition containing the redissolving solvent and the freeze-dried preparation can be prepared on site to obtain a clinical preparation containing the compound 1 or the pharmaceutically acceptable salt thereof when in application, and the preparation combination has the advantages of good solubility and stability, good clinical redissolving effect and the like. The redissolution prescription screened finally by the invention can meet the requirements of multiple aspects such as redissolution time, osmotic pressure, redissolution pH, clarity and the like.
Drawings
FIG. 1 is a graph showing the clarity of the compatible solution (3.2mg/ml) of example 4 at 2-8 ℃ for 0 hours and 26 hours; wherein, in 0 hour, the left bottle is the freeze-dried powder compatible solution, and the right bottle is the 1# turbidity standard solution; in 26 hours, the left bottle is used for sampling and comparing the freeze-dried powder compatible solution, and the right bottle is used for 1# turbidity standard solution.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
EXAMPLE 1 preparation of lyophilized powder of the invention
First, the freeze-drying solution prescription composition (g/bottle)
1-1. Compound 10.1g, alpha-trehalose 1.6g, tert-butanol 9.15g, water for injection 9.15g, appropriate amount of 10N NaOH/5 NHCl.
1-2. compound 10.16 g, alpha-trehalose 2.6g, tert-butyl alcohol 14.6g, water for injection 14.6g, 10N NaOH/5N HCl right amount.
1-3, 10.1g of compound, 2.0g of cane sugar, 10g of ethanol, 10g of water for injection and a proper amount of 10N NaOH/5N HCl.
1-4. Compound 10.1g, mannitol 1.5g, tert-butanol 12.0g, water for injection 12.0g, and appropriate amount of 10N NaOH/5N HCl.
1-5, 10.1g of compound, 0.8g of dextran, 7.0g of tert-butyl alcohol, 7.0g of water for injection and a proper amount of 10N NaOH/5N HCl.
1-6, 10.1g of compound, 1.3g of glucose, 7.0g of tert-butyl alcohol, 7.0g of water for injection and a proper amount of 10N NaOH/5N HCl.
Secondly, taking the example 1-1 as an example, the preparation method comprises the following steps:
1.1 weighing the compound 1 and trehalose in the amount according to the prescription into a suitable container, and marking as a container # 1;
1.2 weighing a batch of tert-butyl alcohol according to a prescription amount, placing the tert-butyl alcohol in a container #1 in the step 1.1, and stirring the tert-butyl alcohol at 40 ℃ until the tert-butyl alcohol is uniformly dispersed;
1.3 weighing a batch of the prescription dose of the injection water and a proper amount of pH regulator, slowly adding the mixture into the container #1 in the step 1.2 while stirring, and stirring until the solution is clear;
1.4, filtering, filling (the theoretical filling amount is 20g, the filling precision is +/-3%), after filling is finished, semi-pressing and filling into a freeze dryer; and (5) freeze-drying to obtain the product.
Examples 1-2 to 1-6 lyophilized powders were prepared by referring to the method of example 1-1.
EXAMPLE 2 development of reconstitution solvent
The injection has a pH value equal to or close to that of blood, and the pH value of the injection is 4-9 required by the common injection in the field; therefore, the pH of the re-dissolved solution is required to be less than 9, the osmotic pressure of the injection is required to be 280-320mOsm/kg, and the injection conforms to the requirement of clarity in Chinese pharmacopoeia (taking the 1# turbidity standard solution as a contrast).
The effect of different co-solvents on the solubility of compound 1 was first investigated. The experimental method comprises the following steps: the resulting solubility was equilibrated at 25 ℃ for 24 hours using an equilibrium solubility assay. The specific results are as follows:
TABLE 1 dissolution of Compound 1 in different solvents
| Solvent(s) | Solubility (mg/mL) | Solvent(s) | Solubility (mg/mL) |
| H2O,pH 1-7 | <0.001 | Ethanol | 0.9 |
| H2O,pH 9 | 0.005 | Propylene glycol | 4.3 |
| H2O,pH 10.6 | 1.1 | PEG400 | 95 |
| Surfactants, ELP | 0.5 | Soybean oil | 0.14 |
| Surfactant, Tween 80 | 0.68 | Oleic acid | 0.03 |
| Surfactant, Solutol HS15 | 1.1 | Ethyl acetate | 0.003 |
| Medium chain triglycerides | 0.004 | Monolinolic acid glyceride | 0.64 |
As can be seen from the data, compound 1 has very low water solubility, non-ideal solubility in most solvents, and maximum solubility in PEG. The PEG in the formulation can provide the solubility requirements of Compound 1, but its amount directly affects the osmotic pressure.
Therefore, there is a major technical challenge to develop a reconstitution solvent capable of reconstituting a lyophilized formulation of compound 1 to simultaneously meet the clinical injection dosing requirements (pH, osmolality, clarity).
The lyophilized powders used in the following development tests were all the lyophilized powders prepared in example 1-1 (0.1g of compound 1/vial), and the amount of the redissolving solvent was 10 ml. The general procedure for reconstitution was as follows: 10ml of solvent are added to the lyophilisate, the phenomenon is observed and the pH is checked. If the sample is clear, the compatibility is carried out, the pH and the osmotic pressure are detected, and the experimental phenomenon and the result are recorded.
Example 2-1
Aiming at the problem of difficult dissolution of the variety, the inventor tries other solutions to solve the problem, and the methods mainly comprise the following modes of observing inclusion by using cyclodextrin, observing complexation by using meglumine, using DMA solvent and the like:
TABLE 2
Wherein, the redissolved solution is clear, but the pH value is over limit, and the redissolution is turbid after the acid is adjusted to be below 9.0.
Examples 2 to 2
Table 3-1 the formulation ratio of the redissolving solvent is as follows:
table 3-2 reconstitution cases are as follows:
although the PEG400, the surfactant ELP and the absolute ethyl alcohol system can achieve the effect of redissolution, the pH and the osmotic pressure after redissolution are both over-limited, and the injection requirement cannot be met.
Examples 2-3 dose prescription adjustment of ethanol
TABLE 4-1
TABLE 4-2
By comparison, the re-dissolving time can be shortened by increasing the dosage of PEG400 and ethanol, but the pH after re-dissolving is over-limited.
Examples 2-4 screening of surfactant, buffer solution
TABLE 5-1
TABLE 5-2
By adjusting the alkali to be sodium bicarbonate water solution (75mmol/L) and the surfactant to be tween 80 and HS-15, the pH and the clarity can meet the requirements, but the osmotic pressure cannot meet the requirements. Therefore, the dosage of PEG400 and the surfactant is reduced, and the dosage of ethanol is increased.
Tables 5 to 3
Tables 5 to 4
| Batch number | pH of redissolving solvent | Reconstitution time | Appearance after redissolving | pH after reconstitution |
| 2-4-6 | 9.13 | ＞5min | Is turbid compared with No. 1 turbidity standard solution | 8.36 |
| 2-4-7 | 9.40 | ＞5min | Is turbid compared with No. 1 turbidity standard solution | 8.53 |
If the dosage of HS15 is only 4.4% w/v, the sample cannot be completely redissolved and clarified, and the prescription design requirement is difficult to achieve in a 4.4% w/v HS15 system.
Examples 2 to 5
To ensure the feasibility of the product, the using amount of HS15 is increased on the basis of ensuring that the daily maximum using amount of the marketed variety is not exceeded, so that the concentration of HS15 in the redissolving solvent reaches 8% w/v, and the design and the results of the experimental prescription are shown below
TABLE 6-1
| Batch number | PEG400(w/v) | HS15(w/v) | Anhydrous ethanol (w/v) | Constant volume solution |
| 2-5-1 | 13％ | 8％ | 8％ | 75mmol/L sodium bicarbonate solution |
| 2-5-2 | 20％ | 8％ | 8％ | 75mmol/L sodium bicarbonate solution |
| 2-5-3 | 15％ | 8％ | 8％ | 75mmol/L sodium bicarbonate solution |
| 2-5-4 | 13％ | 8％ | 8％ | 70mmol/L sodium bicarbonate solution |
| 2-5-5 | 13％ | 8％ | 8％ | 65mmol/L sodium bicarbonate solution |
TABLE 6-2 reconstituted solution status records
It can be seen that the clarity, pH after redissolution and osmotic pressure after dilution of groups 2-5-4 and 2-5-5 can all meet the requirements of the injection.
Example 3
As can be seen from the above-mentioned experiments,
the solubility of the main component in PEG400 is highest, the re-dissolved solution can be clarified by matching with other components in the concentration range of 13% (w/v) to 30% (w/v), but the component has a large contribution to osmotic pressure of the diluted solution, the screening needs to be carried out by combining with other components, and in order to obtain a good prescription ratio, 3 concentrations of 11% (w/v), 13% (w/v) and 15% (w/v) are selected in the test for carrying out the test
② the ethanol dosage is increased to shorten the freeze-dried product redissolution time, and the influence on osmotic pressure and pH value is less.
③ the surfactant may be selected from solubilizing surfactants known in the art. HS-15 as a surfactant can reduce the dosage of PEG400 and alkali in a redissolving solvent, and 3 concentrations of 4% (w/v), 6% (w/v) and 8% (w/v) are selected for screening; optional surfactants are tween 80 and Solutol HS 15; solutol HS15 is adopted in the prescription screening.
And sodium carbonate is adopted to replace sodium bicarbonate, so that the dosage of alkali can be reduced.
According to the pre-experimental result, 4 components in the redissolving solvent are screened based on a multi-factor experiment, and the prescription and the experimental result which meet the requirements of the injection are as follows:
TABLE 7-1
*: water for injection is used as diluent, and the concentration of the diluent is 3.2mg/ml
Therefore, under the conditions, the redissolution solvent formula can meet the requirements of clarification after redissolution, and the pH and osmotic pressure meet the standard requirements.
TABLE 7-2 optimal recipe is 3-5
| Name of raw and auxiliary materials | In mg per ml | Percentage content%, w/v |
| Polyethylene glycol 400 | 110 | 11 |
| HS-15 | 80 | 8 |
| Anhydrous ethanol | 60 | 6 |
| Sodium carbonate | 1.2 | 0.12 |
| Water for injection | Adding to 1ml | Balance of |
The preparation process comprises the following steps: weighing the auxiliary materials according to the prescription respectively, adding PEG400, HS-15 and absolute ethyl alcohol according to the prescription, adding 30% (w/v) of water for injection, mixing uniformly, adding sodium carbonate according to the prescription, stirring for dissolving, finally adding water for injection to a constant volume, stirring for mixing uniformly, and filtering to obtain the compound preparation.
Example 4
And (3) stability test:
weighing the materials according to the optimal formula 3-5, dissolving PEG400, HS-15 and anhydrous ethanol in a 100mL measuring flask, adding a small amount of water, adding a formula amount of sodium carbonate, continuously adding water to dissolve and dilute to scale, filtering with a 0.22 μm hydrophilic PTFE filter membrane,
3.2mg/ml diluent preparation process:
step 1: at room temperature, 2 portions of 10mL redissolving solvent are taken to redissolve 2 bottles of freeze-dried powder prepared in example 1-1 respectively, the redissolution time of each bottle is recorded, the redissolution property of each bottle is observed and compared with turbidity No. 1 standard solution, and the result is shown in attached figure 1.
Step 2: precisely measuring 18ml of the redissolved solution, diluting the redissolved solution to 50ml with water for injection, and independently taking 10ml out for non-liquid phase detection; the remaining sample was used for liquid phase detection.
Examination conditions were as follows: storing at 2-8 deg.C in dark for 8 hr.
And (4) investigation indexes are as follows: character, pH value, content, related substances, osmotic pressure (only 0h)
Investigation time: sampling and detecting at 2-8 deg.C for 0h, 2h, 4h, 6h and 8 h.
TABLE 8 summary of the stability studies of the formulated solutions (3.2mg/ml)
Therefore, the compounded solution can be kept stable within 8 hours at the temperature of 2-8 ℃. The preparation solution has a stability time which is far longer than the administration time (including preparation time, injection administration time and other factors which need to take time), and can realize safe administration clinically.
Claims (10)
1. A formulation combination, characterized in that it comprises: a lyophilized formulation and a reconstituted solvent composition;
the freeze-dried preparation is obtained by freeze-drying a freeze-dried solution comprising the following raw material components: compound 1 or a pharmaceutically acceptable salt thereof, a lyophilized scaffold material, a co-solvent, water, and optionally a pH adjusting agent; the compound 1 has the following structure:
the redissolving solvent composition comprises the following components in percentage by mass and volume (w/v): 10-15% of polyethylene glycol, 3-10% of surfactant, 2-20% of monohydric alcohol containing 1-4 carbon atoms, pH regulator and water, wherein the pH value of the redissolution solvent is 9-12.
2. The formulation combination according to claim 1,
in the raw material components of the freeze-dried preparation, the freeze-dried skeleton material is one or more of glucose, sucrose, xylitol, sorbitol, mannitol, dextran, polyethylene glycol, lactose, raffinose, arginine, glycine, histidine and trehalose;
and/or, in the raw material components of the freeze-dried preparation, the cosolvent is monohydric alcohol containing 1-4 carbon atoms;
and/or in the raw material components of the freeze-dried preparation, the water is deionized water, purified water and water for injection;
and/or, in the raw material components of the lyophilized preparation, the pH regulator is selected from the group consisting of: hydroxide, phosphate, dihydrogen phosphate, citrate, tartrate, arginine, carbonate, bicarbonate, acetate, meglumine, borate, Tris and HCl;
and/or in the raw material components of the freeze-dried preparation, the mass parts of the freeze-dried skeleton material are as follows based on 1 part of the compound 1: 4-20 parts;
and/or in the raw material components of the freeze-dried preparation, the mass parts of the cosolvent are as follows, wherein the mass part of the cosolvent is 1 part of the compound 1: 60-120 parts;
and/or in the raw material components of the freeze-dried preparation, based on 1 part of the compound 1, the water comprises the following components in parts by mass: 60-120 parts;
and/or the freeze-dried preparation is obtained by freeze-drying a freeze-dried solution containing the following raw material components in parts by mass: 1 part of compound 1, 4-20 parts of freeze-dried skeleton material, 60-120 parts of cosolvent and 60-120 parts of water, and optionally a proper amount of pH regulator;
and/or, in the redissolving solvent composition, the polyethylene glycol is selected from polyethylene glycol PEG200-PEG 1000;
and/or, in the redissolving solvent composition, the surfactant is a nonionic surfactant selected from the group consisting of: hydroxystearic acid and polyvinyl alcohol copolymers and analogs thereof, polymers of hydroxy-stearic acid and alpha-hydro-omega-hydroxypoly (oxy-1, 2-ethanediyl) and analogs thereof, polyethylene glycol-15 hydroxystearate and analogs thereof, cholic acid, sodium cholate, tween, span, poloxamer and castor oil polyoxyl ester;
and/or in the redissolving solvent composition, the monohydric alcohol containing 1-4 carbon atoms is one or more of methanol, ethanol, propanol and tert-butanol;
and/or, in the reconstituted solvent composition, the pH adjusting agent is selected from the group consisting of: hydroxides, phosphates, dihydrogen phosphates, citrates, carbonates, hydrogen carbonates and acetates;
and/or in the redissolving solvent composition, the water is deionized water, purified water or water for injection;
and/or in the redissolution solvent composition, the mass volume percentage of the polyethylene glycol is 11-13%;
and/or in the redissolution solvent composition, the mass volume percentage content of the surfactant is 4-8%;
and/or in the redissolution solvent composition, the content of the monohydric alcohol containing 1-4 carbon atoms is 3% -10% by mass volume;
and/or the pH of the redissolving solvent composition is 10-12;
and/or the redissolution solvent composition comprises the following components in percentage by mass and volume: 10-15% of polyethylene glycol, 3-10% of surfactant, 2-8% of monohydric alcohol containing 1-4 carbon atoms, pH regulator and water, wherein the pH of the redissolution solvent is 10-12.
3. The formulation combination of claim 2,
in the raw material components of the freeze-dried preparation, the freeze-dried skeleton material is trehalose;
and/or in the raw material components of the freeze-dried preparation, the cosolvent is one or more of methanol, ethanol, propanol and tert-butanol;
and/or in the raw material components of the freeze-dried preparation, the water is water for injection;
and/or, in the raw material components of the lyophilized preparation, the pH regulator is selected from the group consisting of: sodium hydroxide, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium hydroxide, sodium citrate, sodium carbonate, potassium carbonate, lithium carbonate, sodium bicarbonate, sodium acetate and HCl;
and/or in the raw material components of the freeze-dried preparation, the mass parts of the freeze-dried skeleton material are as follows based on 1 part of the compound 1: 10-20 parts;
and/or in the raw material components of the freeze-dried preparation, the mass parts of the cosolvent are as follows, wherein the mass part of the cosolvent is 1 part of the compound 1: 80-100 parts of a binder;
and/or in the raw material components of the freeze-dried preparation, the mass parts of the water are as follows based on 1 part of the compound 1: 80-100 parts of a binder;
and/or the freeze-dried preparation is obtained by freeze-drying a freeze-dried solution containing the following raw material components in parts by mass: 1 part of compound 1, 10-20 parts of a freeze-dried framework material, 80-100 parts of a cosolvent and 80-100 parts of water, optionally containing a suitable amount of a pH regulator;
and/or, in the re-dissolving solvent composition, the polyethylene glycol is selected from one or more of polyethylene glycol PEG200, PEG300, PEG400 and PEG 600;
and/or, in the solvent composition, when the surfactant is copolymer of hydroxystearic acid and polyvinyl alcohol and the like, the copolymer of hydroxystearic acid and polyvinyl alcohol and the like is copolymer of 12-hydroxystearic acid and polyvinyl alcohol and the like;
and/or, in the reconstitution solvent composition, when the surfactant is a polymer of hydroxy-stearic acid and α -hydro- Ω -hydroxypoly (oxy-1, 2-ethanediyl) and the like, the polymer of hydroxy-stearic acid and α -hydro- Ω -hydroxypoly (oxy-1, 2-ethanediyl) and the like are a polymer of 12-hydroxy-stearic acid and α -hydro- Ω -hydroxypoly (oxy-1, 2-ethanediyl) and the like;
and/or, in the redissolving solvent composition, when the surfactant is polyethylene glycol-15 hydroxystearate and the like, the polyethylene glycol-15 hydroxystearate and the like are polyethylene glycol-15 hydroxystearate
And the like;
and/or, in the reconstituted solvent composition, when the surfactant is tween, the tween is one or more of tween 20, tween 60 and tween 80;
and/or, in the redissolution solvent composition, when the surfactant is span, the span is one or more of span 20, span 60 and span 65;
and/or, in the redissolving solvent composition, when the surfactant is castor oil polyoxyl ester, the castor oil polyoxyl ester is castor oil polyoxyl ester (35);
and/or in the redissolving solvent composition, the monohydric alcohol containing 1-4 carbon atoms is ethanol and/or propanol;
and/or, in the reconstituted solvent composition, the pH adjusting agent is selected from the group consisting of: sodium hydroxide, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium hydroxide, sodium citrate, sodium carbonate, potassium carbonate, lithium carbonate, sodium bicarbonate and sodium acetate;
and/or in the redissolving solvent composition, the water is water for injection;
and/or in the redissolution solvent composition, the content of the monohydric alcohol containing 1-4 carbon atoms is 3% -8% by mass volume;
and/or the pH of the redissolving solvent composition is 11-12;
and/or, in the redissolution solvent composition, when the pH regulator is carbonate, the mass volume percentage of the pH regulator is 0.10-0.15%.
4. The formulation combination of claim 3,
in the raw material components of the freeze-dried preparation, the freeze-dried skeleton material is alpha, alpha-trehalose;
and/or, in the raw material components of the freeze-dried preparation, the cosolvent is tert-butyl alcohol;
and/or, in the raw material components of the freeze-dried preparation, the pH regulator is NaOH and/or HCl;
and/or in the raw material components of the freeze-dried preparation, the mass parts of the freeze-dried skeleton agent are as follows based on 1 part of the compound 1: 16 parts of a mixture;
and/or in the raw material components of the freeze-dried preparation, the mass parts of the cosolvent are as follows, wherein the mass part of the cosolvent is 1 part of the compound 1: 90-92 parts;
and/or in the raw material components of the freeze-dried preparation, the mass parts of the water are as follows based on 1 part of the compound 1: 90-92 parts;
and/or the raw material components of the freeze-dried preparation comprise the following components in parts by mass: 1 part of compound 1, 16 parts of a lyophilized scaffold material, 90-92 parts of a co-solvent, 90-92 parts of water, optionally comprising an appropriate amount of a pH modifier;
and/or, in the redissolving solvent composition, the polyethylene glycol is PEG 400;
and/or, in the redissolving solvent composition, the surfactant is
HS-15；
And/or, in the redissolving solvent composition, the pH regulator is sodium carbonate and/or sodium bicarbonate;
and/or in the redissolution solvent composition, the content of the monohydric alcohol containing 1-4 carbon atoms is 3% -6% by mass volume;
and/or the redissolution solvent composition comprises the following components in percentage by mass and volume: 11-13% of polyethylene glycol, 4-8% of surfactant, 3-6% of monohydric alcohol containing 1-4 carbon atoms, pH regulator and water, wherein the pH value of the redissolution solvent composition is 11-12;
and/or the redissolution solvent composition comprises the following components in percentage by mass and volume: 11% -13% of polyethylene glycol, 4% -8% of surfactant, 4% -8% of monohydric alcohol containing 1-4 carbon atoms, pH regulator and water, wherein the pH value of the redissolution solvent composition is 9-10.
5. The formulation combination according to claim 4,
in the raw material components of the freeze-dried preparation, the pH regulator is 10N NaOH and/or 5N HCl;
and/or in the raw material components of the freeze-dried preparation, the mass parts of the cosolvent are as follows, wherein the mass part of the cosolvent is 1 part of the compound 1: 91.5 parts;
and/or in the raw material components of the freeze-dried preparation, the mass parts of the water are as follows based on 1 part of the compound 1: 91.5 parts;
and/or the freeze-dried preparation is obtained by freeze-drying a freeze-dried solution containing the following raw material components in parts by mass: 1 part of compound 1, 16 parts of alpha, alpha-trehalose, 91.5 parts of tert-butyl alcohol, 91.5 parts of water and a proper amount of pH regulator;
and/or the redissolution solvent composition comprises the following components in percentage by mass and volume: 11% of polyethylene glycol 400, 8% of Solutol HS-15, 6% of absolute ethyl alcohol, 0.12% of sodium carbonate and the balance of water for injection.
6. The formulation combination according to any one of claims 1 to 5,
the redissolution solvent composition is prepared by a preparation method comprising the following steps:
weighing the components of the reconstituted solvent composition according to any one of claims 1-5;
uniformly mixing the polyethylene glycol, the surfactant, the monohydric alcohol containing 1-4 carbon atoms and part of water, adding the pH regulator, dissolving, adding the rest water to a constant volume, and uniformly mixing to obtain the redissolving solvent composition;
and/or, wherein, the freeze-dried preparation is prepared by a preparation method comprising the following steps:
weighing the raw material components of the lyophilized formulation according to any one of claims 1 to 5;
(1) mixing the cosolvent with the compound 1 and the freeze-dried framework material to obtain a mixed solution 1;
(2) mixing the mixed solution 1 with water and a proper amount of pH regulator, and filtering to obtain a solution 2;
(3) filling, freezing and drying to obtain the freeze-dried preparation.
7. A process for preparing a formulation wherein the conditions and operations of said process for preparing a reconstituted solvent composition are as defined in claim 6; the conditions and operations of the process for the preparation of the lyophilized formulation are as described in claim 6.
8. A reconstitution solvent composition for use in a lyophilized formulation, wherein said reconstitution solvent composition is the one described in the formulation combination of any one of claims 1-6.
9. A kit, characterized in that it comprises: one pharmaceutical container containing the lyophilized formulation and the other pharmaceutical container containing the reconstituted solvent composition; the lyophilized formulation and the reconstituted solvent composition are defined as in any one of claims 1-6.
10. The kit of claim 9, wherein the pharmaceutical container is an amber or colorless glass vial with a resilient stopper and a crimped aluminum cap or any amber or colorless container suitable for use in an instant use system; and/or the medicinal container is an ampoule or a penicillin bottle.
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| Title |
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| 罗伯茨: "《近代实验有机化学导论》", 30 April 1981, 上海科学技术出版社 * |
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