CN109394723B - Dutasteride soft capsule and preparation method thereof - Google Patents
Dutasteride soft capsule and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a dutasteride soft capsule with good dissolution, stable quality and good safety, wherein the content components of the dutasteride soft capsule comprise, by weight, 0.076-0.230% of dutasteride, 74.49-91.52% of caprylic triglyceride, 7.31-21.93% of surfactant, 1.08-3.32% of suspending agent and 0.01-0.032% of antioxidant dibutyl hydroxytoluene, and the capsule shell components of the soft capsule comprise 31.86-53.10% of gelatin, 9.56-15.93% of plasticizer glycerol, 1.60-5.31% of disintegrating agent, 0.13-0.22% of opacifier and water. The invention also discloses a preparation process of the dutasteride soft capsule, which effectively improves the dissolution condition and the quality stability of the dutasteride soft capsule by controlling the heating temperature of contents and controlling the drying condition of the soft capsule.
Description
Technical Field
The invention relates to the technical field of pharmaceutical preparations, in particular to an improved dutasteride soft capsule and a preparation method thereof.
Background
Benign Prostatic Hyperplasia (BPH) is one of the high-morbidity species of middle-aged and old men, and dutasteride is one of the mainstream medicines for treating BPH at home and abroad at present. However, the aqueous solubility of the dutasteride raw drug is extremely low (0.908mg/L), and the dissolution rate in water of the preparation is poor, so that the oral bioavailability of the currently marketed dutasteride soft capsule is low (< 60%). The inventor discovers, through research, the reason causing the low dissolution rate of the commercial dutasteride soft capsule, and the reason is related to the unstable quality of the dutasteride soft capsule in the storage period besides the poor water solubility of the dutasteride original drug. Among them, slow disintegration of the soft capsule shell is an important cause of quality instability. A large number of researches show that the slow disintegration of the soft capsule is mainly caused by the cross-linking reaction of gelatin serving as a capsule shell material; among them, aldehyde group is formed by oxidation or autoxidation reaction of amino acid residue in gelatin molecule, and small molecule aldehyde generated by oil phase matrix oxidation is the main reason for gelatin molecule cross-linking.
In view of the above disadvantages and shortcomings of the preparation, the main solution at present is to use common vegetable oil as the oil phase matrix of the contents, and add emulsifier or co-emulsifier to the oil phase matrix for solubilization. According to the technical scheme disclosed by the domestic granted patent ZL201210193189, vegetable oil such as soybean oil is used as an oily matrix, span 80 is used as a surfactant, and the dissolution rate of dutasteride is improved. The solution proposed by the domestic patent CN201210345971 is to use medium chain triglyceride, vegetable oil, etc. as oily substrates, and add emulsifier such as tween 80, polyoxyethylene castor oil, etc. and co-emulsifier such as propylene glycol, etc. to prepare self-microemulsion particles, so as to achieve the purpose of improving the dissolution of dutasteride.
However, it is worth noting that common vegetable oil generally has a special odor, contains a large amount of monounsaturated fatty acids (MUFA) and polyunsaturated fatty acids (PUFA), is unstable in property, and is easily hydrolyzed or oxidized to form substances such as short-chain fatty acids, aldehydes, ketones and the like, which causes the capsule shell of the soft capsule to be crosslinked, thereby affecting the dissolution of the soft capsule. In addition, surfactants such as tween and polyoxyethylene castor oil are easily oxidized and degraded at high temperature due to polyoxyethylene group contained in the molecule to form low molecular aldehyde fragments, which aggravate the crosslinking reaction of gelatin and make the dissolution slow. And it is reported that the polyoxyethylene-based surfactant has a disadvantage of dissolving erythrocyte membrane to cause hemolysis. Meanwhile, tween, span surfactant and the like are reported to cause allergic reaction of human bodies.
Therefore, in the disclosed solutions, it is common practice to add an emulsifier or surfactant to the contents to increase dissolution, but neglecting slow disintegration caused by crosslinking of gelatin of the capsule shell leads to problems of slow dissolution and poor quality stability in the long storage period of the soft capsule, and neglecting the problem of human safety caused by common surfactants. Therefore, a dutasteride soft capsule preparation with good dissolution, stable quality and good safety is not available at present.
Disclosure of Invention
In order to solve the problems of low dissolution rate, slow disintegration and unstable quality in an effective period of the existing commercial dutasteride soft capsule, the inventor provides a dutasteride soft capsule with good dissolution rate, stable quality and good safety and a preparation method thereof through repeated prescription screening and experiments.
In order to solve the technical problems, the idea of the invention is as follows: a Dutasteride soft capsule takes high-purity caprylic triglyceride with good oxidation stability as an oily substrate of a content, takes a compound emulsifier of diglycerol monooleate and decaglycerol monolaurate as a solubilizer, and takes the compound of polyethylene glycol 400, glycine and the like as an disintegration aid in capsule shell components, so that the problems of low dissolution rate and unstable quality of the existing product are obviously improved. Meanwhile, the preparation method of the dutasteride soft capsule is beneficial to improving the dissolution rate of the dutasteride soft capsule and improving the quality stability of the dutasteride soft capsule by controlling the heating temperature in the dutasteride dissolving process and the drying condition of the soft capsule. In addition, the invention selects the pharmaceutical excipients with extremely high safety to human bodies, thereby avoiding the adverse reactions possibly occurring after the human bodies take the pharmaceutical excipients.
The specific technical scheme is as follows:
a dutasteride soft capsule comprises contents and a soft capsule shell.
Wherein, the content comprises the following components in percentage by weight:
wherein, the soft capsule shell comprises the following components in percentage by weight:
wherein said caprylic triglyceride is typically Medium Chain Triglyceride (MCT), more preferably, it is 78.74-87.25% by weight. As is well known in the art, MCT is a colorless, non-irritating, oily liquid at room temperature, which is beneficial to ensure the mouthfeel of soft capsule formulations, while common vegetable oils have special odor and color; meanwhile, MCT is non-toxic and extremely high-safety functional grease. MCT is only composed of saturated fatty acid, has low freezing point and good oxidation stability, and still maintains good oxidation stability at 100 ℃ according to the report of the common cause (1999) research (see table 1), which is obviously superior to common vegetable fat. The inventor finds out through prescription screening that the application of saturated caprylic triglyceride can provide a more stable dispersion system of dutasteride. In the implementation of the invention, the soft capsule taking MCT as the oily matrix has good total impurity content and dissolution rate in accelerated tests and long-term tests, and is superior to the soft capsule taking common vegetable fat as the matrix.
TABLE 1 oxidative stability of MCT and other fats (100 ℃, Raneimat process)
Wherein the surfactant is a mixture of diglycerol monooleate and decaglycerol monolaurate. More preferably a mixture of diglycerol monooleate and decaglycerol monolaurate in a weight ratio of 1-6: 1-2. Both diglycerol monooleate and decaglycerol monolaurate belong to the polyglycerol fatty acid esters. More preferably, the surfactant is present in an amount of 10.98% to 18.28% by weight. As is well known in the art, polyglyceryl fatty acid esters are stable in nature and are not susceptible to hydrolysis under acidic and high temperature conditions; meanwhile, the polyglycerol fatty acid ester has high safety, can participate in metabolism and is utilized by human bodies. In the embodiment of the invention, the dissolution rate of the soft capsule containing the compound emulsifier is obviously superior to that of a commercial dutasteride soft capsule, and is equivalent to that of a soft capsule taking span 80 as a surfactant. The emulsifying property and the hydrophilic property of the polyglycerin fatty acid ester are related to the hydrophilic-lipophilic balance (HLB value) of the polyglycerin fatty acid ester, and the HLB value depends on the polymerization degree of glycerin of the polyglycerin fatty acid ester, the length of a fatty acid carbon chain and the degree of esterification. The inventor finds out in prescription screening that better emulsification effect than a single component can be achieved by compounding polyglycerol fatty acid esters with different polymerization degrees of glycerol and different carbon chain lengths, so that a compounded emulsifier of diglycerol monooleate and decaglycerol monolaurate is preferably used as a surfactant of the content.
The suspending agent is any one or any combination of beeswax, lecithin, aluminum monostearate and ethyl cellulose, more preferably one or any combination of beeswax and lecithin, and most preferably beeswax. The suspending agent is more preferably 2.0 to 2.5 weight percent. The inventor researches to find that when 2.0-2.5% of beeswax by weight is added into the content of the dutasteride soft capsule, the suspension effect and the fluidity of the content are best, so that the invention preferably selects 2.2% of beeswax by weight as a suspending agent.
Wherein, the dibutyl hydroxy toluene (BHT) is an antioxidant of the soft capsule content, and the weight percentage of the dibutyl hydroxy toluene (BHT) in the content is 0.01% -0.032%, and more preferably, the weight percentage of the dibutyl hydroxy toluene (BHT) in the content is 0.015% -0.025%.
Wherein, the glycerol is a plasticizer of the soft capsule shell, and the weight percentage of the glycerol in the soft capsule shell is 9.56-15.93%, and more preferably 11.15-14.34%.
Wherein the disintegrating aid is any one or any combination of polyethylene glycol 400(PEG400), glycine and sodium metabisulfite; the weight percentage of the soft capsule shell is 1.60 to 5.31 percent, and the weight percentage of the soft capsule shell is more preferably 2.61 to 4.30 percent. The disintegrating aid is more preferably a mixture of polyethylene glycol 400(PEG400) and glycine, and the weight ratio of the gelatin to the polyethylene glycol 400 to the glycine is 1: 0.03-0.06: 0.02-0.04. The disintegration assistant provided by the invention has the effects of rapidly disintegrating the soft capsule shell and avoiding slow and low dissolution caused by the capsule shell wrapping active ingredients in contents. The inventor finds that the polyethylene glycol 400(PEG400) has the effect of hardening the capsule shell, the glycine and the sodium metabisulfite have good oxidation resistance and can absorb peroxide in the gelatin and the auxiliary materials, and the compounding of the two components can obviously reduce the crosslinking degree of the gelatin of the soft capsule shell and promote the disintegration of the soft capsule. In one embodiment, the capsule shell prepared according to the capsule shell prescription of the soft capsule provided by the invention has the balance swelling capacity Seq and the disintegration speed which are obviously superior to those of the common gelatin capsule shell, including capsule shells of comparative example and commercial products.
Wherein, the opacifier is a mixture of titanium dioxide and yellow ferric oxide, and the weight percentage of the opacifier in the soft capsule shell is 0.13-0.22%, and more preferably 0.13-0.18%. The proportion of the titanium dioxide and the yellow ferric oxide is not specially limited, and the invention can be realized in any proportion.
Wherein, the content preferably comprises the following components in percentage by weight:
wherein, the soft capsule shell preferably comprises the following components in percentage by weight:
the preparation method of the dutasteride soft capsule comprises the following steps:
(1) preparation of contents: weighing caprylic triglyceride with the prescription amount, heating to 55-65 ℃, adding dutasteride, a surfactant, a suspending agent and dibutyl hydroxy toluene with the prescription amount, stirring until the materials are completely dissolved, and controlling the temperature to be 50-60 ℃;
(2) preparing a soft capsule shell: weighing the glycerol, the disintegration aid, the opacifier and the water according to the formula, heating the mixture to 75-80 ℃ in a gelatin melting tank, uniformly mixing the mixture with the gelatin under the stirring condition, degassing in vacuum, and filtering for later use;
(3) pelleting: the content containing the dutasteride is subpackaged into soft capsules and dried for 45-48 h under the conditions that the temperature is 25-30 ℃ and the humidity is 25-30% RH.
The inventor finds that the dissolution rate of the dutasteride soft capsule can be obviously improved by controlling the heating temperature of the contents and controlling the heating temperature of the raw and auxiliary materials to be 50-60 ℃; meanwhile, the drying condition of the soft capsule is controlled, and the soft capsule is dried for 45-48 hours under the conditions that the temperature is 25-30 ℃ and the humidity is 25-30% RH, so that the stability of the dutasteride soft capsule is improved. In the embodiment of the invention, the dissolution rate of the dutasteride soft capsule prepared by the preparation method is obviously superior to that of a commercial product in short-term storage; under special conditions (high temperature and high humidity) and long-term storage conditions, the dissolution rate, the disintegration speed and the quality stability of the product are all superior to those of a comparative sample and a commercial product.
The invention has the beneficial effects that:
(1) the compound emulsifier of the diglycerol monooleate and the decaglycerol monolaurate is used as a solubilizer, compared with the commercial product of the dutasteride, the dissolution rate and the dissolution rate of the dutasteride soft capsule are obviously improved, the gastrointestinal tract safety of the content of the soft capsule is ensured, and the potential safety hazard possibly brought by tween or span surfactants is avoided.
(2) Caprylic triglyceride with good oxidation stability is used as an oily matrix, so that the phenomenon that the gelatin crosslinking reaction of the soft capsule shell is aggravated due to the oxidation of the oily matrix formed by common oil is avoided; meanwhile, polyethylene glycol 400(PEG400) and glycine and the like in a specific ratio are added into the capsule shell of the soft capsule as disintegration aids, so that the disintegration of the capsule shell of the soft capsule is promoted synergistically, and the problems of poor dissolution and unstable quality of the dutasteride soft capsule in a long storage period due to slow disintegration are solved.
(3) According to the preparation method of the dutasteride provided by the invention, the dissolution rate of the dutasteride soft capsule and the disintegration performance of the capsule shell are improved by controlling the heating temperature of the content of the soft capsule and the drying condition of the soft capsule, so that the quality stability of the dutasteride soft capsule is ensured.
Drawings
FIG. 1 is a graph of dissolution rate over time for various samples.
FIG. 2 shows the dissolution rate of each sample for 20min in the stability test. Wherein: p < 0.05 compared to day 0; compared with 0 day, P is less than 0.01.
Detailed Description
The invention will be better understood from the following examples. However, those skilled in the art will readily appreciate that the description of the embodiments is only for illustrating the present invention and should not be taken as limiting the invention as detailed in the claims.
Examples 1-5 and comparative examples: preparation of dutasteride soft capsule
1. Examples preparation of samples: according to the dutasteride soft capsule prescription in the table 2, which is disclosed by the embodiment 1-5 of the invention, 1000 dutasteride soft capsules are prepared according to the following steps:
(1) preparation of contents: weighing caprylic triglyceride with the prescription amount, heating to 55-65 ℃, adding dutasteride, a surfactant, a suspending agent and dibutyl hydroxy toluene with the prescription amount, stirring until the materials are completely dissolved, and controlling the temperature to be 50-60 ℃;
(2) preparing a soft capsule shell: weighing the glycerol, the disintegration aid, the opacifier and the purified water according to the prescription amount, heating the mixture to 75-80 ℃ in a gelatin melting tank, uniformly mixing the mixture with the gelatin under the stirring condition, degassing in vacuum and filtering for later use;
(3) pelleting: and (3) subpackaging the content containing the dutasteride into soft capsules, drying for 45-48 h under the conditions that the temperature is 25-30 ℃ and the humidity is 25-30% RH, and inspecting the pills after drying to obtain the dutasteride soft capsules.
2. Preparation of comparative example samples: according to the dutasteride soft capsule prescription of the comparative example (ZL201210193189) in table 2, 1000 dutasteride soft capsules are prepared according to the procedure disclosed in the granted patent ZL 201210193189:
weighing dutasteride, oily matrix and surfactant according to a prescription, dissolving and uniformly mixing a small amount of oily matrix, surfactant and dutasteride, adding the rest oily matrix by an equivalent gradual addition method, uniformly mixing to obtain a content, respectively filling the content and a glue solution containing gelatin, water and glycerol into a soft capsule pelleting machine, pelleting, shaping, drying, washing with absolute ethyl alcohol, and finally drying to obtain the dutasteride soft capsule.
TABLE 2 Dutasteride Soft Capsule prescription
Example 6: examination of dissolution rate of dutasteride soft capsule
Sample preparation: each sample was prepared according to examples 1 to 5 and comparative examples and was used. A commercial product of dutasteride with a shelf life similar to that of the prepared sample was purchased for review. The same applies to other examples below.
The investigation method comprises the following steps: according to the basket method in 0391 dissolution and release determination method in 2015 version Chinese pharmacopoeia, the rotation speed is 50 rpm, and 6 granules of the examples and the samples and the Dutasteride soft capsule are respectively taken to perform dissolution determination. The dissolution rate is measured in 900mL of 0.1mol/L hydrochloric acid solution (simulated gastric juice) of 2.0% SDS at 37 +/-0.5 ℃, 5mL is sampled at fixed time at 5min, 10 min, 15 min, 20min, 30min and 45min respectively, the content of dutasteride in the sampled sample is measured by an HPLC method, and the dissolution rate is calculated.
And (4) investigation results:
as can be seen from the results of the dissolution rate test of different samples (see FIG. 1), the dissolution rates of all the samples of the examples and the comparative examples of the invention reach over 80% at 20min, and are obviously higher than those of the commercial products. The dissolution rates of all samples in the embodiments of the invention enter a relatively stable stage after 30min, and reach 90% or more in 45min, which is much higher than that of the commercially available product (71.75%), and is similar to that of the samples in the comparative examples. The Dutasteride soft capsule prepared according to the invention is obviously improved in dissolution rate compared with the commercial product.
Example 7: examination of degree of crosslinking and disintegration time of dutasteride soft capsule
The investigation method comprises the following steps:
(1) treatment of the sample capsule shell: taking the samples of the examples, the samples of the comparative examples and the commercial products, cutting the soft capsule samples along the middle seam, extruding the content, washing the capsule shell for 3 times by using absolute ethyl alcohol, and drying the capsule shell at room temperature until the water content is about 10 percent for later use.
(2) Measurement of equilibrium swelling capacity (Seq): different samples were placed at 40 ℃ and RH 75% for 3 months and sampled periodically. Taking 6 pieces of sample film from capsule shell of different samples, labeling, precisely weighing, swelling in 500m1 distilled water at 20 deg.C, taking out the film after 1, 2, 2.5, 3, 3.5, 4 hr, wiping off surface liquid with filter paper, and precisely weighing. And drying 6 tablets at 105 ℃ to constant weight, calculating the water content of the film, solving the initial dry weight of the capsule shell, and calculating the Seq by regression according to the following formula:
wherein
Wt is the weight of the film at t time, Wi is the initial dry weight of the rubber;
wherein K is the swelling rate constant. As can be seen from the formula, the value of Seq can be determined by the slope B of the t/s-t line.
(3) Determination of disintegration time (D): different samples were left at 40 ℃ and RH 75% for 3 months, sampled at regular intervals, and the disintegration time (D) of the different samples was measured using a disintegration tester.
And (4) investigation results:
TABLE 3 results of examination of the equilibrium swelling capacity and disintegration time of the samples
From the results of examining the equilibrium swelling capacity (Sep) and disintegration time (see Table 3) of the different samples, it can be seen that the crosslinking degree (higher Sep value, lower crosslinking degree) and disintegration time of the soft capsules on day 30 are similar between the example and the comparative example and the commercially available product, but on day 60 and day 90, Sep of the example is significantly higher than that of the comparative example and the commercially available product, and disintegration time is significantly lower than that of the comparative example and the commercially available product. The dutasteride soft capsule prepared according to the invention has obviously improved crosslinking degree and disintegration time of the soft capsule shell compared with the comparative sample and the commercial products.
Example 8: quality stability investigation
The investigation method comprises the following steps: taking 6 soft capsules of different samples, respectively placing for 10 days at 50 ℃, 10 days at normal temperature and humidity RH 92.5%, and 10 days under illumination 4500Lux to carry out accelerated stability test, placing for 3 months under conditions of 30 ℃ +/-2 ℃/65% RH +/-5% RH to carry out long-term stability test, and respectively measuring the total impurity content and 20min dissolution rate of different samples after the test is finished.
And (4) investigation results:
table 4 formulation stability study total impurity content results (N ═ 6)
Note: p < 0.05 compared to day 0; p < 0.01 compared to day 0.
From the results of the study and investigation of the stability of the formulations of the different samples (see table 4), it can be seen that all samples remained stable in the long-term test, and the total impurity content was not significantly different from 0 day; in the accelerated test, under the condition of strong light (light irradiation of 4500Lux, 10 days), the samples of examples 1 and 2, the comparative sample and the commercial product all have a remarkable increase of the total impurity content, but the increase of the impurity content of the sample of the experimental example is smaller than that of the commercial product and the comparative sample. In addition, the experimental sample remained stable for total impurities under other conditions, while the commercial product showed a significant increase in impurities (P < 0.05) under still higher temperature conditions, and the comparative sample showed a significant increase in total impurities (P < 0.05) under the remaining accelerated test conditions. In general, the impurity stability of the experimental sample is better than that of the comparative sample and the commercial product. Among them, in view of the fact that the oily base (caprylic triglyceride) of the experimental sample and the oily base (caprylic capric acid mono-diglyceride) of the commercial product are both high-purity medium-chain triglycerides, while the oily base of the comparative sample is common soybean oil, the main component of which is unsaturated fatty acid, and the high-purity medium-chain triglycerides have great advantages as the oily base.
In terms of dissolution rate for stability studies (see fig. 2), the example samples remained more stable at the 20min dissolution rate for the relevant study conditions as a whole than the comparative samples and the commercial products. In the long-term test, the dissolution rate of the sample of the example is relatively stable, and the sample of the comparative example and the commercial product have a remarkable downward slip (P is less than 0.05 compared with 0 day). In the accelerated test, only the experiment example 1 in the experiment example samples has a significant slip (P is less than 0.05) of the dissolution rate of 20min under the strong light condition, and other experiment example samples keep the dissolution rate stable; while the comparative example showed a significant (P < 0.05) or very significant (P < 0.01) slip-off at 20min dissolution rate under all accelerated test conditions, the commercial product showed a significant (P < 0.05) slip-off under conditions other than high humidity. In conclusion, the soft dutasteride capsule prepared according to the embodiment of the invention has better quality stability than the comparative sample and the commercial product.
Claims (6)
1. The dutasteride soft capsule comprises a content and a soft capsule shell, and is characterized in that the content comprises the following components in percentage by weight:
wherein the surfactant is a mixture of diglycerol monooleate and decaglycerol monolaurate in a weight ratio of 1-6: 1-2;
wherein the suspending agent is any one or any combination of beeswax, lecithin, aluminum monostearate and ethyl cellulose.
2. The dutasteride soft capsule of claim 1, wherein the suspending agent is beeswax, and the suspending agent accounts for 2.0-2.5% of the weight of the contents.
3. The dutasteride soft capsule according to claim 1, wherein the content comprises the following components by weight percent:
4. a dutasteride soft capsule according to any one of claims 1-3, characterized in that the soft capsule shell comprises the following components by weight percent:
wherein, the disintegration aid is any one or any combination of polyethylene glycol 400, glycine and sodium metabisulfite; when the disintegrating aid is a mixture of polyethylene glycol 400 and glycine, the weight ratio of the gelatin to the polyethylene glycol 400 to the glycine is 1: 0.03-0.06: 0.02-0.04;
wherein the opacifier is a mixture of titanium dioxide and yellow ferric oxide.
5. The dutasteride soft capsule according to claim 4, wherein the soft capsule shell is composed of the following components by weight percent:
6. the preparation method of the dutasteride soft capsule of claim 4, which is characterized by comprising the following steps:
(1) preparation of contents: weighing caprylic triglyceride with the prescription amount, heating to 55-65 ℃, adding dutasteride, a surfactant, a suspending agent and dibutyl hydroxy toluene with the prescription amount, stirring until the materials are completely dissolved, and controlling the temperature to be 50-60 ℃;
(2) preparing a soft capsule shell: weighing the glycerol, the disintegration aid, the opacifier and the water according to the formula, heating the mixture to 75-80 ℃ in a gelatin melting tank, uniformly mixing the mixture with the gelatin under the stirring condition, degassing in vacuum, and filtering for later use;
(3) pelleting: the content containing the dutasteride is subpackaged into soft capsules and dried for 45-48 h under the conditions that the temperature is 25-30 ℃ and the humidity is 25-30% RH.
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