CN109394724B - Butylphthalide liquid hard capsule preparation and preparation method thereof - Google Patents
Butylphthalide liquid hard capsule preparation and preparation method thereof Download PDFInfo
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Abstract
The invention provides a butylphthalide liquid hard capsule, which comprises a capsule shell and contents, wherein the contents comprise butylphthalide and vegetable oil; the weight ratio of the butyl phthalide to the vegetable oil is 1:0 to 10. The butyl phthalide liquid hard capsule has the advantages of small disintegration time change, stable quality, high dissolution speed, quick effect, and good compatibility between the content and the capsule shell.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a butylphthalide liquid hard capsule preparation and a preparation method thereof.
Background
Butylphthalide, chemical name is 3-butyl-l (H) -isobenzofuranone, also called apigenin, is racemate extracted from celery seeds, and can also be artificially synthesized; in chinese patent CN1100097, an application of apigenin in the preparation of a medicament for preventing and treating diseases caused by cerebral ischemia of mammals or humans is disclosed, wherein apigenin is butylphthalide without optical activity, butylphthalide is oily liquid, has strong celery flavor, and has a chemical structural formula shown in formula 1:
butylphthalide for improving NO and PGI of cerebrovascular endothelium2The level of the compound can reduce the intracellular calcium concentration, inhibit the release of glutamic acid, reduce the content of arachidonic acid, inhibit oxygen free radicals, improve the activity of antioxidant enzyme and the like, and act on a plurality of pathological links caused by cerebral ischemia. Due to the excellent therapeutic effect of butylphthalide, it was formally listed in the Chinese guideline for acute ischemic stroke 2010 in 2010The guiding medication of cerebral arterial thrombosis.
The butyl phthalide soft capsule (trade name: enbipro) is a national class new drug developed by the stone drug group, is marketed in 2003, and is proved by the research result of evidence-based medicine through clinical application of nearly ten years that the enbipro can effectively improve the neurological deficit of patients with ischemic stroke, and has few adverse reactions.
With the clinical large-scale application of the butylphthalide soft capsule, the problems that the preparation process of the soft capsule is complex, and the requirements on the proficiency of workers are high in the process of preparing the rubber and pressing particularly appear; ② in the soft capsule storage process, the capsule shell aging leads to the disintegration time extension, and then leads to slow dissolution speed, slow effect, for acute stroke patients, 6 hours after the onset of disease is the best treatment time, the effect in advance is each minute has very important meaning, although butyl phthalide sodium chloride injection has been on the market, its dissolution is fast, the effect is fast, can solve the above-mentioned problems, but the use is not as convenient as the oral preparation such as soft capsule.
At present, except the butyl phthalide soft capsule, no other oral preparations are on the market, and no products and related reports of the butyl phthalide liquid hard capsule exist. In view of the medicinal value of butylphthalide, the oral formulation of butylphthalide still needs to be studied to develop a new formulation to meet the clinical requirement.
Disclosure of Invention
The inventor is dedicated to the development of a butylphthalide medicinal preparation for a long time, and develops a new formulation of butylphthalide, namely a butylphthalide liquid hard capsule, aiming at the specific physicochemical property of butylphthalide and combining the development and theory of pharmacy.
The invention aims to provide a butylphthalide liquid hard capsule with fast drug release and dissolution speed and good stability.
The invention also aims to provide a preparation method of the butylphthalide liquid hard capsule, which is simple and convenient to operate.
The invention adopts the following technical scheme:
a butylphthalide liquid hard capsule comprises a hard capsule shell and contents, wherein the contents comprise butylphthalide and vegetable oil; the weight ratio of the butylphthalide to the vegetable oil is 1: 0-10.
Preferably, the ratio of the butyl phthalide to the vegetable oil in the butyl phthalide liquid hard capsule is 1: 1-8.
More preferably, the butylphthalide liquid hard capsule comprises 1: 2-5 of butylphthalide and vegetable oil.
More preferably, in the above liquid hard capsule of butylphthalide, the ratio of butylphthalide to vegetable oil is 1: 3.5.
The liquid hard capsule of butylphthalide is prepared from one or more of oleum Sesami, oleum Maydis, oleum Arachidis Hypogaeae, soybean oil, oleum Armeniacae amarum, oleum Persicae, oleum gossypii semen, oleum Helianthi, and oleum Olivarum.
The above butylphthalide liquid hard capsule can also be added with a cosolvent, wherein the cosolvent is one or more of span 20, span 60, span 80, glyceryl behenate, glyceryl monolinoleate, propylene glycol monocaprylate, propylene glycol monolaurate, glyceryl monooleate, high-purity diethylene glycol monoethyl ether, linoleic acid polyethanol-6 glyceride, lauric acid polyethanol-6 glyceride, medium-chain triglyceride, caprylic capric acid glyceride, caprylic capric acid propanediol ester, propylene glycol fatty acid ester, polyglycerol oleate and oleic acid polyethylene glycol glyceride.
According to the butylphthalide liquid hard capsule, an antioxidant can be added into the content, wherein the antioxidant is any one pharmaceutically acceptable antioxidant, and preferably one or more of tocopherol, lecithin, citric acid, ascorbic acid, hydroxyanisole and butylated hydroxytoluene. If added, the antioxidant is present in a weight ratio of from 0.01% (based on butylphthalide) to 0.1% (based on butylphthalide), preferably from 0.025% (based on butylphthalide) to 0.05% (based on butylphthalide). The addition of the antioxidant further hinders the degradation of butylphthalide, and the content of degradation products is further reduced; meanwhile, the rancidity of the vegetable oil is hindered, and the validity period of the butyl phthalide liquid hard capsule is prolonged.
The term "pharmaceutically acceptable" as used herein means that the substance does not produce unacceptable toxicity to the subject or interact with other components of the liquid hard capsule.
The capsule shell of the liquid hard capsule is an important component of the liquid hard capsule preparation, effectively isolates the medicine from contacting with the outside, protects the content in the capsule shell, prevents or weakens the oxidation of the content, and makes the content more stable. The inventor of the present invention has conducted a great deal of experiments to study various capsule shells of hard capsules sold in the market, and as a result, found that the capsule shell of hard capsules mainly comprising gelatin and HPMC (hydroxypropyl methylcellulose, the same below) has good compatibility with the content of butylphthalide. The HPMC is preferably 2906, 2910 and 2208 in type.
The invention also discloses a preparation method of the butylphthalide liquid hard capsule, which comprises the steps of weighing the components according to the formula proportion, stirring, dissolving and uniformly mixing to obtain a mixture, namely the content, filling the content into a hard capsule shell, and sealing to obtain the butylphthalide liquid hard capsule.
The butylphthalide liquid hard capsule provided by the invention is stored for 6 months under the conditions of 40 ℃ and 75% RH (relative humidity, the same below), and the disintegration time limit is within 8min (minutes, the same below); the content contains not more than 0.2% (based on butylphthalide) of degradation products and/or specific degradation products.
The butylphthalide liquid hard capsule provided by the invention is stored for 24 months under the conditions of shading and room temperature, the disintegration time limit is within 8min (minutes, the same below), and the content comprises degradation products which are not higher than 0.2 percent (calculated by butylphthalide) and/or specific degradation products.
The butylphthalide liquid hard capsule provided by the invention is stored for 36 months under the conditions of shading and room temperature, the disintegration time limit is within 8min (minutes, the same below), and the content comprises degradation products which are not higher than 0.2 percent (calculated by butylphthalide) and/or specific degradation products.
The butylphthalide liquid hard capsule provided by the invention is stored for 48 months under the conditions of shading and room temperature, the disintegration time limit is within 8min (minutes, the same below), and the content comprises degradation products which are not higher than 0.2 percent (calculated by butylphthalide) and/or specific degradation products.
The butylphthalide refers to a racemate, a levorotatory isomer or a dextrorotatory isomer thereof.
The liquid hard capsules of butylphthalide are also suitable for oil-soluble butylphthalide derivatives.
Compared with the prior art, the invention has the beneficial effects that:
(1) compared with the butyl phthalide soft capsule, the butyl phthalide liquid hard capsule has the advantages of more transparency, more beautiful appearance and easier acceptance by patients.
(2) The production process is simple, the operation is convenient, the butylphthalide liquid hard capsule is produced by directly injecting the butylphthalide content into a commercially available hollow capsule shell and sealing the shell, the butylphthalide soft capsule is produced by injecting the butylphthalide content into a self-made soft capsule shell through a pill press for pressing, the soft capsule shell needs to be dried for 10-40 hours after pressing through the steps of gelatin melting, sol melting, vacuumizing for bubble removal, heat preservation, filtering and the like, and therefore, the production process of the butylphthalide soft capsule is complex to control, long in period and high in requirement on the proficiency of workers; from the perspective of large-scale production, the liquid hard butyl phthalide capsule is superior to the soft butyl phthalide capsule.
(3) Temperature and humidity, the butyl phthalide liquid hard capsule does not contain plasticizers such as glycerin, sorbitol and the like, is insensitive to temperature and humidity, has stable quality in the processes of transportation, storage and use, the capsule shell of the butyl phthalide soft capsule contains the plasticizers such as glycerin, sorbitol and the like, is sensitive to temperature and humidity, and the conditions are strictly controlled in the processes of transportation, storage and use.
(4) The disintegration time limit of the butylphthalide liquid hard capsule is small in change, stable in quality, high in dissolution speed and quick in effect in the storage process; in the soft capsule, the capsule skin contains plasticizers such as glycerin, sorbitol and the like, so that the capsule skin is easy to age and the disintegration time limit is greatly changed; slow dissolution and slow effect.
(5) Compatibility with butylphthalide content: the liquid hard capsule shell has good compatibility with the butyl phthalide content, the degradation products are reduced in the storage process, the stability of the content is improved, and the effective period is prolonged.
The butylphthalide liquid hard capsule combines the novel dosage form of the liquid hard capsule with the innovative medicine of butylphthalide, further enhances the clinical use of butylphthalide, and is a great gospel for the patients with acute ischemic stroke.
Drawings
FIG. 1: content of butylphthalide in digestive tract content of rat
The abscissa: time (unit: time)
Ordinate: amount of butylphthalide in digestive tract content (unit: mg)
Detailed Description
The invention discloses a butylphthalide liquid hard capsule and a preparation method thereof, and can be realized by properly improving process parameters or prescription ratio by taking the contents of the invention as reference and combining the principle of pharmacy by technical personnel in the field. It is expressly intended that all such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the scope of the invention. While the invention has been described in terms of preferred embodiments, it will be apparent to those skilled in the art that variations may be applied, or changes and combinations may be made, in the methods and applications described herein to achieve and use the inventive techniques without departing from the spirit, scope, and content of the invention.
The present invention is further illustrated by the following examples, which are not intended to limit the invention in any way.
Comparative example 1: butylphthalide soft capsule, prior art product, is prepared according to the prescription and preparation method disclosed in Chinese patent CN1623542
1) The prescription composition is as follows:
the composition of the contents is as follows: 100g of butylphthalide and 350g of soybean oil
The capsule skin comprises the following components: 100g of gelatin, 30g of glycerol, 130kg of water and 200mg of ethylparaben
2) The preparation method comprises the following steps:
a. preparation of capsule shell solution: adding appropriate amount of water into gelatin to make it absorb water and expand, adding the rest water, glycerol and ethylparaben into gelatin melting barrel, heating to 70-80 deg.C, adding expanded gelatin after reaching the temperature to make it completely dissolve, vacuumizing to remove bubbles during dissolving process, and keeping the temperature for use;
b. preparation of the contents: mixing butyl phthalide and soybean oil, and dissolving;
c. pressing the soft capsules: and pressing the content and the capsule shell solution into a soft capsule, strictly controlling the environmental temperature to be 18-22 ℃ and the environmental humidity to be 10-20% RH in the pressing process, drying for 10-40 h, and packaging, wherein each capsule contains 100mg of butylphthalide.
6 batches were prepared according to the above recipe composition and preparation method.
Comparative example 2: butylphthalide soft capsule, prior art product, is prepared according to the prescription and preparation method disclosed in Chinese patent CN1726909
1) The prescription composition is as follows:
the composition of the contents is as follows: 100g of butylphthalide, 50g of polyethylene glycol-8 glyceryl caprylate/caprate and 50g of polyoxyethylene castor oil
The capsule skin comprises the following components: 100g of gelatin, 30g of glycerol, 130kg of water and 200mg of ethylparaben
2) The preparation method comprises the following steps:
a. preparation of capsule shell solution: adding appropriate amount of water into gelatin to make it absorb water and expand, adding the rest water, glycerol and ethylparaben into gelatin melting barrel, heating to 70-80 deg.C, adding expanded gelatin after reaching the temperature to make it completely dissolve, vacuumizing to remove bubbles during dissolving process, and keeping the temperature for use;
b. preparation of the contents: mixing butyl phthalide, polyethylene glycol-8 glyceryl caprylate/caprate, and polyoxyethylene castor oil, and dissolving;
c. pressing the soft capsules: and pressing the content and the capsule shell solution into a soft capsule, strictly controlling the environmental temperature to be 18-22 ℃ and the environmental humidity to be 10-20% RH in the pressing process, drying for 10-40 h, and packaging, wherein each capsule contains 100mg of butylphthalide.
Comparative example 3: accelerated test
A proper amount of the sample of the comparative example 1-2 is stored for 6 months under the conditions that the temperature is 40 +/-2 ℃ and the relative humidity is 75 +/-5%, samples are taken at the end of 1 st, 2 nd, 3 th and 6 th months respectively, and the properties, the disintegration time limit, related substances and the content are measured, and the results are shown in Table 1.
The "related substance" in the present invention includes impurities such as a degradation product of butylphthalide, a specific degradation product and the like.
Table 1: comparative examples 1-2 sample accelerated test results
Comparative example 4: long term experiment
A proper amount of the samples in comparative examples 1-2 are stored for 48 months under the conditions that the temperature is 25 +/-2 ℃ and the relative humidity is 60 +/-10%, samples are taken at the end of 3 rd, 6 th, 9 th, 12 th, 18 th, 24 th, 36 th and 48 th months respectively, and the properties, disintegration time limit, related substances and content are measured, and the results are shown in Table 2.
Table 1: comparative examples 1-2 Long-term test results
Example 1: butylphthalide liquid hard capsule
1) The prescription composition is as follows:
the composition of the contents is as follows: 100g of butylphthalide and 350g of soybean oil;
the liquid hard capsule shell comprises the following main components: gelatin
2) The preparation method comprises the following steps:
a. preparation of the contents: weighing the components of the content according to the proportion of the prescription, stirring, dissolving and uniformly mixing to obtain a mixture, namely the content;
b. filling a liquid hard capsule: filling the content into the hard capsule shell, and sealing to obtain the butylphthalide liquid hard capsule. Each granule contains 100mg of butylphthalide;
6 batches were prepared according to the above recipe composition and preparation method.
Example 2: butylphthalide liquid hard capsule
1) The prescription composition is as follows:
the composition of the contents is as follows: 100g of butylphthalide;
the liquid hard capsule shell comprises the following main components: gelatin;
2) the preparation method comprises the following steps: the same as in example 1.
Example 3: butylphthalide liquid hard capsule
1) The prescription composition is as follows:
the composition of the contents is as follows: 100g of butylphthalide and 500g of soybean oil;
the liquid hard capsule shell comprises the following main components: gelatin;
2) the preparation method comprises the following steps: the same as in example 1.
Example 4: butylphthalide liquid hard capsule
1) The prescription composition is as follows:
the composition of the contents is as follows: 100g of butylphthalide and 200g of soybean oil;
the liquid hard capsule shell comprises the following main components: HPMC (2906);
2) the preparation method comprises the following steps: the same as in example 1.
Example 5: butylphthalide liquid hard capsule
1) The prescription composition is as follows:
the composition of the contents is as follows: 100g of butylphthalide and 800g of sunflower seed oil;
the liquid hard capsule shell comprises the following main components: HPMC (2910);
2) the preparation method comprises the following steps: the same as in example 1.
Example 6: butylphthalide liquid hard capsule
1) The prescription composition is as follows:
the composition of the contents is as follows: 100g of butylphthalide and 400g of olive oil;
the liquid hard capsule shell comprises the following main components: HPMC (2208);
2) the preparation method comprises the following steps: the same as in example 1.
Example 7: butylphthalide liquid hard capsule
1) The prescription composition is as follows:
the composition of the contents is as follows: 100g of butylphthalide and 400g of soybean oil;
the liquid hard capsule shell comprises the following main components: gelatin;
2) the preparation method comprises the following steps: the same as in example 1.
Example 8: butylphthalide liquid hard capsule
1) The prescription composition is as follows:
the composition of the contents is as follows: 100g of butylphthalide and 700g of sesame oil;
the liquid hard capsule shell comprises the following main components: gelatin;
2) the preparation method comprises the following steps: the same as in example 1.
Example 9: butylphthalide liquid hard capsule
1) The prescription composition is as follows:
the composition of the contents is as follows: 100g of butylphthalide and 350g of peanut oil;
the liquid hard capsule shell comprises the following main components: gelatin;
2) the preparation method comprises the following steps: the same as in example 1.
Example 10: butylphthalide liquid hard capsule
1) The prescription composition is as follows:
the composition of the contents is as follows: 100g of butylphthalide and 1000g of peanut oil;
the liquid hard capsule shell comprises the following main components: gelatin;
2) the preparation method comprises the following steps: the same as in example 1.
Example 11: butylphthalide liquid hard capsule
1) The prescription composition is as follows:
the composition of the contents is as follows: 100g of butylphthalide, 350g of soybean oil and 450g of polyglycerol oleate;
the liquid hard capsule shell comprises the following main components: gelatin;
2) the preparation method comprises the following steps: the same as in example 1.
Example 12: butylphthalide liquid hard capsule
1) The prescription composition is as follows:
the composition of the contents is as follows: 100g of butylphthalide, 350g of soybean oil, 200g of polyglycerol oleate and 150g of polyethylene glycol oleate;
the liquid hard capsule shell comprises the following main components: gelatin;
2) the preparation method comprises the following steps: the same as in example 1.
Example 13: butylphthalide liquid hard capsule
1) The prescription composition is as follows:
the composition of the contents is as follows: 100g of butylphthalide, 400g of soybean oil and 0.05g of tocopherol;
the liquid hard capsule shell comprises the following main components: HPMC (2208);
2) the preparation method comprises the following steps: the same as in example 1.
Example 14: butylphthalide liquid hard capsule
1) The prescription composition is as follows:
the composition of the contents is as follows: 100g of butylphthalide, 500g of soybean oil and 0.05g of butylated hydroxytoluene;
the liquid hard capsule shell comprises the following main components: HPMC (2906);
2) the preparation method comprises the following steps: the same as in example 1.
Example 15: butylphthalide liquid hard capsule
1) The prescription composition is as follows:
the composition of the contents is as follows: 100g of butylphthalide, 800g of peanut oil and 60g of propylene glycol fatty acid ester;
the liquid hard capsule shell comprises the following main components: HPMC (2910);
2) the preparation method comprises the following steps: the same as in example 1.
Example 16: butylphthalide liquid hard capsule
1) The prescription composition is as follows:
the composition of the contents is as follows: 100g of butylphthalide, 400g of olive oil and 450g of propylene glycol monocaprylate;
the liquid hard capsule shell comprises the following main components: HPMC (2906);
2) the preparation method comprises the following steps: the same as in example 1.
Example 17: butylphthalide liquid hard capsule
1) The prescription composition is as follows:
the composition of the contents is as follows: 100g of butylphthalide, 200g of soybean oil, 200g of glycerol monooleate and 0.025g of tocopherol
The liquid hard capsule shell comprises the following main components: HPMC (2208);
2) the preparation method comprises the following steps: the same as in example 1.
Example 18: butylphthalide liquid hard capsule
1) The prescription composition is as follows:
the composition of the contents is as follows: 100g of butylphthalide, 700g of soybean oil, 30g of glyceryl behenate and 0.025g of butylated hydroxytoluene;
the liquid hard capsule shell comprises the following main components: gelatin;
2) the preparation method comprises the following steps: the same as in example 1.
Example 19: butylphthalide liquid hard capsule
1) The prescription composition is as follows:
the composition of the contents is as follows: 100g of butylphthalide, 350g of peanut oil, 250g of glycerol monolinoleate and 350g of propylene glycol monolaurate;
the liquid hard capsule shell comprises the following main components: gelatin;
2) the preparation method comprises the following steps: the same as in example 1.
Example 20: butylphthalide liquid hard capsule
1) The prescription composition is as follows:
the composition of the contents is as follows: 100g of butylphthalide, 500g of peanut oil, 150g of medium chain triglyceride and 300g of caprylic capric glyceride;
the liquid hard capsule shell comprises the following main components: gelatin;
2) the preparation method comprises the following steps: the same as in example 1.
The difference of the preparation process of the soft capsule and the liquid hard capsule is as follows:
as can be seen from the above table; the production process of the soft capsule is complex to control, long in period and high in requirement on the proficiency of workers; from the perspective of mass production, the liquid hard capsule, butylphthalide soft capsule, was analyzed.
Example 21 accelerated test
A proper amount of the samples of examples 1 to 20 were stored at 40 ℃. + -. 2 ℃ and a relative humidity of 75%. + -. 5% for 6 months, and samples were taken at the end of 1 st, 2 nd, 3 th and 6 th months, and the properties, disintegration time, related substances and contents thereof were measured, and the results are shown in tables 3-1 to 3-3.
Table 3-1: example 1 to 7 accelerated test results of samples
Tables 3-2: example 8 to 14 accelerated test results of samples
Tables 3 to 3: example 15 to 20 accelerated test results
As can be seen from the data in tables 3-1 to 3-3: the butylphthalide liquid hard capsule provided by the invention is stored for 6 months under an accelerated condition, the disintegration time limit is basically kept unchanged, and is within 8min within about 6 min; the content comprises not more than 0.2% (calculated by butylphthalide) of degradation products andor specific degradation products; the compatibility of the butylphthalide content and the liquid hard capsule shell is good.
Comparing the results of table 1 and table 3, it can be seen that: the butylphthalide liquid hard capsule is quick in disintegration, quick in dissolution and quick in effect, and meanwhile, the content butylphthalide and the capsule shell of the liquid hard capsule are compatible, compared with the butylphthalide soft capsule, the butylphthalide hard capsule is remarkably improved, and the butylphthalide liquid hard capsule is stable in quality and can meet the requirements of clinical use.
Example 22: long term experiment
A proper amount of the samples of examples 1 to 20 were stored at 25 ℃. + -. 2 ℃ and a relative humidity of 60%. + -. 10% for 48 months, and samples were taken at the end of 3 rd, 6 th, 9 th, 12 th, 18 th, 24 th, 30 th, 36 th and 48 th months, respectively, and the properties, disintegration time, related substances and contents thereof were measured, and the results are shown in tables 4-1 to 4-5.
Table 4-1: long-term experimental results of samples of examples 1 to 4
Tables 4-2: example 5-8 Long-term test results of samples
Tables 4 to 3: example 9-12 Long-term test results for samples
Tables 4 to 4: results of long-term experiments on samples of examples 13 to 16
Tables 4 to 5: example 17-20 Long-term test results of samples
As can be seen from the data in tables 4-1 to 4-5:
the butylphthalide liquid hard capsule provided by the invention is stored for 24 months under a long-term condition, and the disintegration time limit is prolonged from 5.6min (average value in 0 month) to 6.2min (average value in 24 months), which shows that the capsule shell is stable and the disintegration of the medicine is not influenced; the related substances are increased from 0.11% (average value in 0 month) to 0.16% (average value in 24 months), which shows that the compatibility of the contents of the butylphthalide liquid hard capsule and the hard capsule shell is better; that is, the composition can be stored for 24 months under long-term conditions, and has disintegration time within 8min (min, the same below), and the content contains not more than 0.2% (calculated as butylphthalide) of degradation product and/or specific degradation product
The butylphthalide liquid hard capsule provided by the invention is stored for 36 months under a long-term condition, and the disintegration time limit is prolonged from 5.6min (average value of 0 month) to 6.6min (average value of 36 months), which shows that the capsule shell is stable and the disintegration of the medicine is not influenced; the related substances are increased from 0.11% (average value in 0 month) to 0.17% (average value in 36 months), which shows that the compatibility of the contents of the butylphthalide liquid hard capsule and the hard capsule shell is good; i.e. for 36 months under long-term conditions, with a disintegration time of within 8min (minutes, the same applies hereinafter) and said contents comprising not more than 0.2% (calculated as butylphthalide) of degradation products and/or specific degradation products.
The butylphthalide liquid hard capsule provided by the invention is stored for 48 months under a long-term condition, and the disintegration time limit is prolonged from 5.6min (average value of 0 month) to 7.1min (average value of 48 months), which shows that the capsule shell is stable and the disintegration of the medicine is not influenced; the related substances are increased from 0.11% (average value of 0 month) to 0.18% (average value of 36 months), which shows that the compatibility of the contents of the butylphthalide liquid hard capsule and the hard capsule shell is very good; i.e., 48 months under long-term conditions, and a disintegration time of within 8min (minutes, the same applies hereinafter) when the composition is disintegrated, said composition containing not more than 0.2% (in terms of butylphthalide) of a degradation product and/or a specific degradation product.
Comparing the results of table 2 with table 4, it can be seen that: the butylphthalide liquid hard capsule is fast in disintegration, fast in dissolution and fast in effect, the compatibility between the content butylphthalide and the capsule shell of the liquid hard capsule is good, and the butylphthalide liquid hard capsule is stable in quality and can meet the requirements of clinical use.
In examples 13, 14, 17 and 18, the antioxidant is added, and the data of the four examples (examples 13, 14, 17 and 18) and the data of the other examples are compared, we can see that: the antioxidant is added to hinder the degradation of butylphthalide, the content of related substances (degradation products or specific degradation products) is further reduced, and the content contains no more than 0.15% (based on butylphthalide) of degradation products and/or specific degradation products when stored for 48 months under long-term conditions.
Statistical analysis of comparative example 1 and example 1 data
The formula of the comparative example 1 is the same as that of the example 1, the difference is that the capsule shell is different, and the capsule shell of the butylphthalide soft capsule is adopted in the comparative example 1; example 1 using butylphthalide liquid hard capsule shells, 6 batches of each were prepared and subjected to long-term experiments to compare the differences by statistical data analysis.
(1) Data source
Preparing 6 batches of butylphthalide soft capsules according to the prescription of the comparative example 1 and the preparation method, and storing for 48 months under long-term conditions; samples were taken at the end of 0 month, 3 months, 6 months, 9 months, 12 months, 18 months, 24 months, 36 months and 48 months, and the properties, disintegration time, related substances and contents thereof were measured. The data results are shown in table 2.
6 batches of butylphthalide liquid hard capsules were prepared according to the formulation and preparation method of example 1 and stored for 48 months under long-term conditions; samples were taken at the end of 0 month, 3 months, 6 months, 9 months, 12 months, 18 months, 24 months, 36 months and 48 months, and their properties, disintegration time, related substances and contents were measured, and the data results are shown in Table 4.
(2) Data analysis method
Two groups of data stored for the same time are subjected to statistical analysis, and whether the disintegration time limit and related substances have significant differences or not is analyzed.
Data are expressed as mean ± standard deviation (X ± S) and analyzed using SPSS11.5 statistical software. Student-Newman-Keuls tests were performed using one way ANOVA for comparisons between groups at the same time period.
(3) Analysis results
The analysis results are shown in tables 5 and 6.
Table 5: statistical analysis result table of disintegration time limit in long-term experiment of comparative example 1 and example 1
Table 6: relevant substance statistical analysis result table in long-term experiment of comparative example 1 and example 1
As can be seen from table 5: the initial (0 month) disintegration time limit of the butyl phthalide soft capsule and the butyl phthalide liquid hard capsule is not different (P is more than 0.05), and the disintegration time limit is obviously different (P is less than 0.01) after the butyl phthalide soft capsule and the butyl phthalide liquid hard capsule are stored for 3 months; the liquid butyl phthalide hard capsule has obvious progress in disintegration time limit compared with the butyl phthalide soft capsule.
As can be seen from table 6: the butyl phthalide soft capsule and the butyl phthalide liquid hard capsule have no difference (P >0.05) in relative substances at the beginning of preparation (0 month) and after 3 months of storage, and have difference (P <0.05) after 6 months of long-term storage; after 9 months of long-term storage, the related substances have significant difference (P < 0.01); the butyl phthalide liquid hard capsule has obvious progress in the aspect of related substances compared with the butyl phthalide soft capsule.
Example 23: effect on absorption by rats
1. Animal model: adult male SD rats, 200-250 g in mass, were divided into two groups of 12 rats each:
(1) butyl phthalide soft capsule group: orally stored 24 months butylphthalide soft capsule (100mg)1 granule
(2) Butyl phthalide liquid hard capsule group: oral storage 24 months butyl phthalide liquid hard capsule (100mg)1 granule
Respectively at 0.5 hour, 1 hour, 2 hours, 3 hours, 5 hours, 6 hours, 8 hours, 10 hours and 12 hours
Detecting the content of butylphthalide in the contents of the digestive tract at regular time, 18 hours and 24 hours.
2. And (3) test results: see attached figure 1
The abscissa: time (unit: time)
Ordinate: amount of butylphthalide in digestive tract content (unit: mg)
As can be seen from FIG. 1 in conjunction with Table 1: the absorption curves of the butylphthalide liquid hard capsule and the butylphthalide soft capsule are similar; the butylphthalide liquid hard capsule has short disintegration time, so the butylphthalide liquid hard capsule can be absorbed in the gastrointestinal tract quickly; the butylphthalide soft capsule has long disintegration time, so that the butylphthalide soft capsule can be absorbed in gastrointestinal tract slowly. And for the disease with a narrow treatment time window, namely acute cerebral apoplexy, the capsule has very important significance every minute in advance, so that the butylphthalide liquid hard capsule is obviously superior to the butylphthalide soft capsule in the aspect of absorption.
Claims (4)
1. The butyl phthalide liquid hard capsule comprises a hard capsule shell and contents, wherein the contents are as follows: 100g of butylphthalide, 500g of soybean oil and 0.05g of butylated hydroxytoluene; the hard capsule shell mainly comprises HPMC 2906.
2. The butyl phthalide liquid hard capsule comprises a hard capsule shell and contents, wherein the contents are as follows: 100g of butylphthalide, 700g of soybean oil, 30g of glyceryl behenate and 0.025g of butylated hydroxytoluene; the main component of the hard capsule shell is gelatin.
3. The butyl phthalide liquid hard capsule comprises a hard capsule shell and contents, wherein the contents are as follows: 100g of butylphthalide, 400g of soybean oil and 0.05g of tocopherol; the main component of the hard capsule shell is HPMC 2208.
4. The butyl phthalide liquid hard capsule comprises a hard capsule shell and contents, wherein the contents are as follows: 100g of butylphthalide, 200g of soybean oil, 200g of glycerol monooleate and 0.025g of tocopherol; the main component of the hard capsule shell is HPMC 2208.
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US20060051409A1 (en) * | 2004-09-08 | 2006-03-09 | Groenewoud Pieter J | Bezonatate liquid hard capsule dosage form |
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US20060051409A1 (en) * | 2004-09-08 | 2006-03-09 | Groenewoud Pieter J | Bezonatate liquid hard capsule dosage form |
CN101991557A (en) * | 2009-08-10 | 2011-03-30 | 杭州赛利药物研究所有限公司 | Liquid vancomycin hydrochloride capsule and preparation method thereof |
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