CN114767633B - Solid dispersion containing anti-breast cancer medicament tamoxifen, preparation method and preparation - Google Patents
Solid dispersion containing anti-breast cancer medicament tamoxifen, preparation method and preparation Download PDFInfo
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- 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
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
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- 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
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- 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
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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
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
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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
Abstract
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a tamoxifen solid dispersion, a preparation method and a preparation thereof. The invention solves the problem of low dissolution rate caused by poor solubility of tamoxifen by a solid dispersion technology, and also solves the problem that the solid dispersion is easy to age, thereby improving the stability of the solid dispersion and the preparation.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a solid dispersion containing an anti-breast cancer medicament tamoxifen, a preparation method and a preparation.
Background
The breast cancer is a phenomenon that mammary epithelial cells generate uncontrolled proliferation under the action of various carcinogenic factors. The early stage of the disease often shows symptoms such as breast lumps, nipple discharge, axillary lymphadenectasis and the like, and the later stage of the disease can generate distant metastasis due to cancer cells to generate multi-organ lesion, which directly threatens the life of a patient. The recent clinical treatment shows that the ten-year survival rate of the breast cancer averagely reaches 60%, the survival rate after the first-stage breast cancer treatment reaches 80%, and the survival rate after the zero-stage breast cancer treatment is closer to 100%, so the early-stage discovery and treatment are very important.
Tamoxifen, chemical name (Z) -2- [4- (1,2-diphenyl-1-butene) phenoxy]-N, N-dimethylethylamine is an organic compound of formula C 26 H 29 NO, clinically useful for the treatment of advanced breast and ovarian cancer. The effective rate of clinical treatment of breast cancer is generally 30%, the curative effect of estrogen receptor positive patients is better (49%), and the curative effect of negative patients is poor (7%). Both premenopausal and postmenopausal patients can use the composition, while postmenopausal and above 60 years of age are more effective than premenopausal and young patients. The curative effect of skin, lymph nodes and soft tissues is good from the focus position.
However, due to the problem of poor water solubility of tamoxifen, which directly affects the absorption and utilization of the drug, the solid oral drug must be absorbed by considering the dissolution of the drug in the gastrointestinal tract, and the drug usually dissolves in the gastrointestinal tract to form a molecular state before being absorbed through the mucosa of the gastrointestinal tract. Thus, dissolution of the drug is a prerequisite for its absorption in the gastrointestinal tract.
The solid dispersion is a dispersion system in solid form formed by uniformly dispersing the drug in a carrier in a highly dispersed state such as a molecular, amorphous, microcrystalline state and the like. As an intermediate of a pharmaceutical preparation, the solid dispersion technology can increase the solubility and dissolution rate of a poorly soluble drug, and is beneficial to improving the bioavailability of the drug.
Chinese patent CN101732235A discloses a citrate acid tamoxifen solid dispersion, which consists of tamoxifen citrate, polyethylene glycol-6000 and a flow aid, wherein the weight ratio of the tamoxifen citrate to the polyethylene glycol-6000 is 1:4.5-12.5. The patent utilizes a solid dispersion technology to prepare the tamoxifen citrate solid dispersion, and further prepares common tablets, dispersible tablets, sustained release tablets, capsules and other oral solid preparations with high bioavailability and good absorbability, so that the dissolution rate of the tamoxifen citrate reaches over 90 percent, but the problem of poor stability of the dispersed state of the medicine is not solved, and the aging phenomenon is easily caused after long-term storage, such as the dissolution reduction of a dispersion system, the content increase of related substances and other problems.
Disclosure of Invention
The problem of low dissolution caused by poor solubility of tamoxifen is solved by a solid dispersion technology in the prior art, but the problem of easy aging of the solid dispersion is not properly solved, for example, the problems of low dissolution, incomplete dissolution, increase of related substance content and the like after long-term storage are solved.
Specifically, the technical scheme and the technical effects of the invention are as follows:
firstly, in order to solve the problem of poor water solubility of tamoxifen, the invention utilizes a solid dispersion technology, utilizes the entrapment of a carrier, and uses the drug in the carrier to exist in a highly dispersed state to increase the dissolution rate of the drug. Through repeated research and a large number of experiments, the inventor finds that the hydrophilic carrier is more suitable for being used in the solid dispersion technology of tamoxifen, and the hydrophilic carrier can increase the solubility and dissolution rate of the insoluble drug and is more helpful for improving the bioavailability of the drug. By further optimization, the dissolution improving effect is better in a form of combining sugar alcohol hydrophilic carriers and surfactant hydrophilic carriers, so that the invention provides a solid dispersion containing tamoxifen, which comprises tamoxifen, sugar alcohol hydrophilic carriers and surfactant hydrophilic carriers.
However, the sugar alcohol hydrophilic carrier has a very large number of choices, such as mannitol, erythritol, xylitol, sorbitol, galactose, fructose, etc., and the inventors found through a one-factor test that the effect of increasing dissolution can be achieved by uniformly dispersing tamoxifen in mannitol, erythritol, xylitol, sorbitol, galactose, fructose, or a combination of mannitol, erythritol, xylitol, sorbitol, galactose, fructose, or a plurality of combinations thereof, and particularly when erythritol is selected as the sugar alcohol hydrophilic carrier, the effect is more excellent, for example, erythritol contains 4 hydrogen bond acceptors, the number of hydrogen bond acceptors is 4, and the sugar alcohol hydrophilic carrier often contains a plurality of hydroxyl groups, and has a strong hydrogen bond effect, and easily forms hydrogen bonds of X-H … Y in space to form a skeleton structure, and inhibits drug precipitation crystals. Similarly, the inventor screens surfactant hydrophilic carriers through a single-factor test, poloxamer, polyoxyethylene and carbopol are all suitable for a dispersion system of tamoxifen, and especially poloxamer 188 is selected as the surfactant hydrophilic carrier, so that the dissolution of tamoxifen can be increased.
Furthermore, the inventor artificially finds a more suitable carrier matrix of the solid dispersion system of the tamoxifen, summarizes the dosage proportion of the tamoxifen, sugar alcohol hydrophilic carriers and surfactant hydrophilic carriers through a large number of experiments, and controls the proportion of the tamoxifen and the carrier matrix within the range of 1:3-11, thereby ensuring the drug-loading rate of the tamoxifen in the dispersion system and improving the encapsulation rate of the tamoxifen; in particular, in tamoxifen: sugar alcohol hydrophilic carrier: surfactant-based hydrophilic carrier: the weight ratio of the organic acid is 1: (1-5): (2-6), in particular tamoxifen: sugar alcohol hydrophilic carrier: surfactant-based hydrophilic carrier: the weight ratio of the organic acid is 1:2:3, the good solubility of the whole tamoxifen solid dispersion system can be ensured, the high drug loading of the tamoxifen solid dispersion can be ensured, and the quality of the solid dispersion system can be improved to the greatest extent.
Secondly, since the drug in the carrier of the solid dispersion system exists in a highly dispersed state, the drug dispersion state is high, the solubility is improved and the absorbability is enhanced, the physical stability is poor, the aging phenomenon is easy to occur after long-term storage, the content of related substances is easy to be increased due to degradation after long-term storage, and the situations of reduced solubility and incomplete dissolution of the preparation are easy to occur. In order to solve the defect of the solid dispersion, the inventor finds that the group of 2- (N, N-dimethyl) ethoxy in tamoxifen is easy to degrade from the structure of the compound and the overall characteristics of the solid dispersion system, so that the inventor can inlay into an erythritol-poloxamer carrier skeleton by adding organic acids such as citric acid, malic acid, tartaric acid, quinic acid and oxalic acid, especially organic matters with carboxyl such as malic acid, to the solid dispersion system to form a more stable solid dispersion system. Single factor experiments prove that the malic acid has stronger capability of being embedded into a carrier skeleton and better effect of stabilizing a dispersion system, particularly tamoxifen: sugar alcohol hydrophilic carrier: surfactant-based hydrophilic carrier: the weight ratio of the organic acid is 1:2:3: when 0.1, the effect was excellent in terms of drug loading, encapsulation efficiency, leakage rate, and the content of the relevant substance.
Third, the present invention provides a method for preparing the above solid dispersion containing tamoxifen. The method commonly used for producing a solid dispersion includes a melting method, a solvent-melting method, a solvent spray freeze-drying method, a milling method, and the like, but not every method is applicable to the above dispersion system, and it is necessary to judge the state of the solid dispersion by physical characterization. The inventor prepares solid dispersions according to the formula by five methods, namely a melting method, a solvent-melting method, a solvent spray freeze-drying method and a grinding method, and performs characterization and quality control on the obtained solid dispersion of tamoxifen by means of solubility, DSC, infrared and the like, and finds that the solid dispersion prepared by the solvent method has higher mixing uniformity and is not easy to crystallize. Specifically, the preparation method of the solid dispersion containing tamoxifen provided by the invention comprises the following steps: dissolving tamoxifen, sugar alcohol hydrophilic carriers and surfactant hydrophilic carriers in a proper amount of organic solvent, heating and rotary steaming in water bath at 25 ℃ for 10-30min, slowly adding a proper amount of organic acid solution dissolved in the organic solvent, continuing heating and rotary steaming in water bath at 25-40 ℃ for 2-4h, evaporating the organic solvent to obtain a coprecipitate, washing and drying to obtain the solid dispersion of tamoxifen.
Furthermore, the inventor verifies the influence of the type of the organic solvent on the quality of the prepared solid dispersion of tamoxifen through a single-factor test, and the experiments are respectively carried out by selecting ethanol, acetonitrile, methanol, the mixed solvent, the ethanol aqueous solution, the acetonitrile aqueous solution and the methanol aqueous solution, so that the obtained solid dispersion of tamoxifen can reach the quality standard, and particularly, the ethanol is used as the organic solvent, so that the yield is higher, and the preparation of subsequent preparations is more facilitated. In addition, the inventor also controls the water bath heating temperature, and single factor experiments show that the temperature is gradually increased at constant temperature of 25 ℃,30 ℃, 35 ℃ and 40 ℃ and 25-40 ℃, and the solid dispersion of tamoxifen can be obtained under the temperature control conditions, especially the temperature is gradually adjusted from 25-40 ℃ according to the speed of distillate, so that the preparation time can be shortened, the tamoxifen and the carrier are subjected to rotary evaporation for 10min, the organic acid is added for 2h, and the solid dispersion of tamoxifen can be obtained after subsequent washing and other steps, so that the time is saved, the efficiency is improved, and the energy consumption is reduced.
Fourthly, the solid dispersion containing tamoxifen prepared by the invention can be prepared into preparations with pharmaceutically acceptable auxiliary materials, wherein the preparations include but are not limited to tablets, capsules, granules, pills, powder, suspensions and oral liquids.
Drawings
FIG. 1: (a) Schematic representation of tamoxifen-sugar alcohol-surfactant solid dispersion; (b) Schematic representation of tamoxifen-sugar alcohol-surfactant-organic acid solid dispersion
FIG. 2: examples 2 and 4 of the present invention and dissolution of commercially available preparations in different media
FIG. 3: encapsulation efficiency of tamoxifen solid dispersion
FIG. 4: the tamoxifen solid dispersion has the dissolution condition stored at the relative humidity of 60%, the temperature of 4 ℃,25 ℃ and the temperature of 40 ℃ for 6 months
FIG. 5: content of relevant substances of tamoxifen solid dispersion
FIG. 6: example 2, example 4, comparative example 2 and commercial tamoxifen tablets for the relevant substance content
Detailed Description
In order to make the purpose and technical solutions of the present invention more clearly understood, the present invention is further described with reference to the following examples, but the scope of the present invention is not limited to these examples, and the examples are only used for explaining the present invention. It will be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the true scope of the invention.
Example 1 preparation of tamoxifen solid dispersion
The preparation method comprises the following steps:
dissolving tamoxifen, sugar alcohol hydrophilic carriers and surfactant hydrophilic carriers in a proper amount of ethanol, heating and rotary steaming for 2-4h in a water bath at 25-40 ℃, gradually adjusting the temperature from 25-40 ℃ according to the speed of a distillate, steaming out an organic solvent to obtain a coprecipitate, washing and drying to obtain a solid dispersion of tamoxifen, wherein the drug-loading rate is 14.7 +/-0.3%.
Example 2 tamoxifen tablets (100 tablets)
The preparation method comprises the following steps:
the tamoxifen solid dispersion prepared in example 1, the filler, the disintegrant and the glidant are respectively crushed, sieved, uniformly mixed and tabletted according to the formula.
Example 3 preparation of tamoxifen solid dispersion
The preparation method comprises the following steps:
dissolving tamoxifen, sugar alcohol hydrophilic carriers and surfactant hydrophilic carriers in a proper amount of ethanol, heating and rotary steaming for 10-30min in a water bath at 25 ℃, slowly adding a proper amount of organic acid solution dissolved in the ethanol, continuing heating and rotary steaming for 2-4h in a water bath at 25-40 ℃, gradually adjusting the temperature from 25-40 ℃ according to the speed of a distillate, steaming out an organic solvent to obtain a coprecipitate, washing and drying to obtain the solid dispersion of the tamoxifen, wherein the drug loading is 15.9 +/-0.2%.
Example 4 tamoxifen tablets (100 tablets)
The preparation method comprises the following steps:
the tamoxifen solid dispersion prepared in example 3, the filler, the disintegrant and the glidant are respectively crushed, sieved, uniformly mixed and tabletted according to the formula.
Comparative example 1:
a solid dispersion of tamoxifen citrate acid prepared according to example 1 in the specification of Chinese patent CN 101732235A.
Comparative example 2:
a common tablet of tamoxifen citrate prepared according to example 2 of the specification of Chinese patent CN 101732235A.
EXAMPLE 5 dissolution of formulations in different media
When the dissolution comparison of the tamoxifen tablets prepared in the embodiments 2 and 4 of the present invention and a reference preparation (commercially available tamoxifen tablets) was performed, in vitro dissolution experiments were performed in a medium with pH =1.2, a medium with pH =4.5, a medium with pH =6.8, and water, respectively, and the results showed that the tamoxifen tablets of the present invention could be well dissolved in four different media, and the dissolution rates within 30min all reached 97% or more (fig. 2).
Example 6 characterization of solid Dispersion by solubility method
| Weight ratio of | Solubility in water | ||
| A | Tamoxifen as starting material | —— | 0.09±0.03g/l |
| B | Tamoxifen-erythritol-poloxamer 188 physical mixture | 1:2:3 | 0.16±0.11g/l |
| C | Tamoxifen-erythritol-poloxamer 188 solid Dispersion | 1:2:3 | 2.57±0.34g/l |
| D | Tamoxifen-erythritol-poloxamer 188 solid dispersion | 1:1:2 | 2.48±0.28g/l |
| E | Tamoxifen-erythritol-poloxamer 188 solid dispersion | 1:5:6 | 2.51±0.26g/l |
| F | Tamoxifen-erythritol-poloxamer 188 solid dispersion | 1:7:1 | 1.64±0.17g/l |
| G | Tamoxifen-mannitol-polyoxyethylene solid dispersion | 1:2:3 | 2.32±0.22g/l |
| H | Tamoxifen-erythritol-poloxamer 188-malic acid solid dispersion | 1:2:3:0.1 | 2.89±0.14g/l |
| I | Tamoxifen-erythritol-poloxamer 188-citric acid solid dispersion | 1:2:3:0.1 | 2.81±0.16g/l |
| J | Tamoxifen-polyethylene glycol solid dispersion | 1:5 | 0.41±0.05mg/l |
| K | Comparative example 1 | —— | 1.21±0.20g/l |
The solubility method is used for carrying out physical characterization on the solid dispersion, the solubility of the solid dispersion is only improved by 1.7 times after the tamoxifen and the carrier material are physically mixed, the solubility of the solid dispersion prepared by optimizing the carrier material and a certain proportion is obviously improved by 32 times of the solubility of the tamoxifen, and the dissolution of the tamoxifen can be further improved through the improvement of the solubility, so that the bioavailability is improved.
Example 7 solid Dispersion encapsulation efficiency exploration
A: tamoxifen: erythritol: poloxamer 188=1 (weight ratio)
B: tamoxifen: erythritol: poloxamer 188=1 (weight ratio)
C: tamoxifen: erythritol: poloxamer 188=1
D: tamoxifen: erythritol: poloxamer 188=1 (weight ratio)
E: tamoxifen: polyethylene glycol =1:5 (weight ratio)
F: tamoxifen: erythritol: poloxamer 188: malic acid =1
G: tamoxifen: erythritol: poloxamer 188: malic acid =1
H: tamoxifen: erythritol: poloxamer 188: malic acid =1
I: tamoxifen: polyethylene glycol: malic acid =1
The formula dosage and preparation process of groups A to E were the same as those of group 1,F-I in example 3, and three parallel experiments were performed to prepare tamoxifen solid dispersion and determine the encapsulation efficiency. (FIG. 3)
Example 8 aging Studies of tamoxifen solid Dispersion-dissolution
The aging degree of the tamoxifen solid dispersion in example 1, the tamoxifen solid dispersion in example 3 and the tamoxifen solid dispersion in comparative example 1 were tested by simulating the change of dissolution rate after long-term storage under the condition of relative humidity of 60% and storing at 4 ℃,25 ℃ and 40 ℃ for 6 months, respectively, so as to test the stability of the drug intermediate-tamoxifen solid dispersion.
Dissolution conditions: taking 1000ml of 0.02mol/L hydrochloric acid solution as dissolution medium, rotating at 100 rpm, and sampling respectively for 5min, 10min, 15min, 20min and 30min according to the method. The determination method comprises the following steps: 10ml of the dissolution liquid is taken and filtered, and the subsequent filtrate is taken. Measuring the absorbance at 275nm by UV-visible spectrophotometry as C 26 H 29 The elution amount of each tablet was calculated as 311 for the absorption coefficient of NO.
FIG. 4 shows that temperature affects the dissolution of solid dispersion of tamoxifen, for example, in example 2, selecting a suitable carrier material to form solid dispersion with tamoxifen has less dissolution change when stored at 4 deg.C, 25 deg.C, 40 deg.C for 6 months; for example, in example 4, a suitable carrier material is selected, and a suitable amount of organic acid is added to form a solid dispersion with tamoxifen, so that the problem of incomplete dissolution caused by aging of the solid dispersion can be effectively prevented, and quality assurance is provided for further preparation of the preparation.
Example 9 tamoxifen solid dispersion aging degree study-related substance content
The aging degree of the tamoxifen solid dispersion is researched by simulating the content of the related substances after long-term storage, the tamoxifen solid dispersion in the groups A to F is placed for 6 months under the conditions of 40 +/-2 ℃ and 75% +/-5% of relative humidity, and samples are respectively taken at the end of 1 month, 2 months, 3 months and 6 months during the test period to test the content of the related substances, so that the stability of the tamoxifen solid dispersion as a drug intermediate is researched.
A: example 1
B: tamoxifen: erythritol: poloxamer 188: malic acid =1
C: tamoxifen: erythritol: poloxamer 188: malic acid =1
D: tamoxifen: erythritol: poloxamer 188: malic acid =1
E: tamoxifen: polyethylene glycol: malic acid =1
F: comparative example 1
Wherein, the formula dosage and the preparation process of the groups B-E are the same as those of the example 3, and the tamoxifen solid dispersion is prepared.
The determination method comprises the following steps: measuring by high performance liquid chromatography (general rule 0512). The preparation was carried out in the dark and used for new preparation. Test solution: taking a proper amount of fine powder (about 50mg of tamoxifen) of the product, precisely weighing, placing in a 50ml measuring flask, adding a proper amount of mobile phase, carrying out ultrasonic treatment for 5 minutes, cooling, diluting to a scale with the mobile phase, shaking up, centrifuging, and taking supernatant. Control solution: precisely measuring a proper amount of the test solution, and quantitatively diluting with a mobile phase to obtain a solution containing 5 mug of the test solution in each 1 ml. Control solution: taking an impurity I (tamoxifen E-isomer) reference substance, precisely weighing, adding a mobile phase for dissolution, and quantitatively diluting to prepare a solution containing about 7.5 mu g of impurity I per 1 ml. System applicability solution: the control solution and the control solution are mixed in equal amount. Chromatographic conditions are as follows: octadecylsilane chemically bonded silica is used as a filling agent, phosphate buffer solution (0.9 g of sodium dihydrogen phosphate and 4.8g of N, N-dimethyl octylamine are taken, water is added for dissolving and diluting into 1000ml, and phosphoric acid is used for adjusting the pH value to 3.0) -acetonitrile (60: 40) is used as a mobile phase; the detection wavelength is 240nm; the injection volume was 10. Mu.l. System applicability requirements: in the system applicability solution chromatogram, the number of theoretical plates is not less than 2000 calculated according to an impurity I peak, and the separation degree of the impurity I peak and a main component peak (tamoxifen Z-isomer) is more than 3.0. The determination method comprises the following steps: precisely measuring the test solution, the reference solution and the reference solution, respectively injecting into a liquid chromatograph, and recording the chromatogram until the retention time of the main component peak is 2 times. Limitation: if a peak which is consistent with the retention time of the impurity I (tamoxifen E-isomer) peak in the chromatogram of the reference solution exists in the chromatogram of the test solution, the peak area of the peak is not larger than the main peak area (0.75%) of the reference solution.
As shown in fig. 5, the tamoxifen solid dispersion of example 1 (group a) of the present invention has better stability, and the content of impurity I (tamoxifen E-isomer) in the accelerated test is only 0.1%, further, the tamoxifen solid dispersion prepared by adding organic acid into groups B-E has higher stability, especially the content of tamoxifen: sugar alcohol hydrophilic carrier: surfactant-based hydrophilic carrier: the weight ratio of the organic acid is 1: (1-5): (2-6): (0.1-0.5), the content of the impurity I (tamoxifen E-isomer) is lower, and the problem of high content of related substances caused by aging of the solid dispersion can be effectively inhibited by adding a proper amount of organic acid, so that excellent quality control guarantee is provided for further preparing the preparation.
Example 10 substance content study of tamoxifen tablets
Accelerated tests and long-term tests were carried out on the tablets of example 2, example 4, comparative example 2 and commercially available tamoxifen, respectively, according to the above-mentioned methods for determining substances.
And (3) accelerated test: according to the commercial package, the test piece is placed for 6 months under the conditions that the temperature is 40 +/-2 ℃ and the relative humidity is 75% +/-5%, and samples are respectively taken at the end of 1 month, 2 months, 3 months and 6 months during the test period to measure the content of related substances.
And (3) long-term test: according to the commercial package, the sample is placed under the conditions that the temperature is 25 +/-2 ℃ and the relative humidity is 60% +/-10%, and the samples are respectively taken at 0 month, 3 months, 6 months, 9 months, 12 months, 24 months and 36 months during the test period, and the content of the related substances is detected.
As shown in fig. 6, the growth rules of the content of the relevant substances in the long-term test and the accelerated test are basically consistent, and the content of impurities in the tamoxifen tablet prepared in example 2 of the present invention is low, which indicates that the preparation further prepared by using a solid dispersion technology by selecting a suitable carrier material has high stability, and particularly, as in example 4, the organic acid is introduced into the solid dispersion technology, so that the content of impurities in the preparation is significantly reduced, the preparation stability is further improved, and the effective period of the pharmaceutical product is prolonged.
Example 11 investigation of the preparation method
According to the formulation of example 1, 5 methods of a melting method, a solvent-melting method, a solvent spray freeze-drying method and a grinding method are respectively used for preparing the tamoxifen solid dispersion, and the solubility of the prepared tamoxifen solid dispersion is tested.
| Preparation method | Solubility in water |
| Melting process | 1.01±0.45g/l |
| Solvent process | 2.57±0.32g/l |
| Solvent-melt process | 1.66±0.35g/l |
| Solvent spray freeze-drying method | 0.98±0.27g/l |
| Grinding method | 0.52±0.13g/l |
According to the formulation of example 4, 5 methods of melting method, solvent-melting method, solvent spray freeze-drying method and grinding method were used to prepare tamoxifen solid dispersion, and the solubility of the prepared tamoxifen solid dispersion was tested.
| Preparation method | Solubility in water |
| Melting process | 1.35±0.33g/l |
| Solvent process | 2.89±0.14g/l |
| Solvent-melt process | 1.87±0.36g/l |
| Solvent spray freeze-drying method | 1.21±0.31g/l |
| Grinding method | 0.58±0.15g/l |
Therefore, the interaction between tamoxifen and a carrier material in the solid dispersion prepared by the medium-solvent method is more sufficient, the dispersibility is better, and the solubility is higher.
Claims (4)
1. The solid dispersion containing tamoxifen is characterized by comprising tamoxifen, erythritol, poloxamer 188 and an organic acid in a weight ratio of: erythritol: poloxamer 188: the organic acid ratio is 1:1-5:2-6;
the solid dispersion is prepared by adopting a solvent method: dissolving tamoxifen, erythritol and poloxamer 188 in an appropriate amount of ethanol, heating and rotary steaming in a water bath at 25 ℃ for 10-30min, slowly adding an organic acid solution dissolved in an appropriate amount of ethanol, continuing heating and rotary steaming in a water bath at 25-40 ℃ for 2-4h, gradually adjusting the temperature from 25-40 ℃ according to the speed of a distillate, evaporating the ethanol to obtain a coprecipitate, washing, and drying to obtain the solid dispersion of tamoxifen.
2. The solid dispersion of claim 1, wherein the organic acid is one of citric acid and malic acid.
3. The solid dispersion of claim 1, wherein the tamoxifen: erythritol: poloxamer 188: the weight ratio of organic acid is 1.
4. A formulation prepared from the tamoxifen-containing solid dispersion of claim 1, wherein the formulation further comprises pharmaceutically acceptable excipients; the preparation is one of tablets, capsules, granules, pills, powder, suspensions and oral liquid.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101732235A (en) * | 2010-01-19 | 2010-06-16 | 上海复旦复华药业有限公司 | Solid dispersion of tamoxifen citrate, method for preparing same and application thereof |
| CN102885813A (en) * | 2004-08-27 | 2013-01-23 | 拜尔保健公司 | Pharmaceutical compositions for the treatment of hyper-proliferative disorders |
| CN109925314A (en) * | 2018-11-15 | 2019-06-25 | 沈阳药科大学 | A kind of RALOXIFENE HCL phosphatide complexes solid dispersions and its preparation |
| WO2021187289A1 (en) * | 2020-03-16 | 2021-09-23 | Ricoh Company, Ltd. | Method for producing particles |
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| BRPI0908340A2 (en) * | 2008-02-28 | 2018-12-26 | Bial Portela & Ca Sa | pharmaceutical composition for poorly soluble drugs |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102885813A (en) * | 2004-08-27 | 2013-01-23 | 拜尔保健公司 | Pharmaceutical compositions for the treatment of hyper-proliferative disorders |
| CN101732235A (en) * | 2010-01-19 | 2010-06-16 | 上海复旦复华药业有限公司 | Solid dispersion of tamoxifen citrate, method for preparing same and application thereof |
| CN109925314A (en) * | 2018-11-15 | 2019-06-25 | 沈阳药科大学 | A kind of RALOXIFENE HCL phosphatide complexes solid dispersions and its preparation |
| WO2021187289A1 (en) * | 2020-03-16 | 2021-09-23 | Ricoh Company, Ltd. | Method for producing particles |
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