CN109620810B - Huperzine A composition tablet and preparation method thereof - Google Patents
Huperzine A composition tablet and preparation method thereof Download PDFInfo
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4748—Quinolines; Isoquinolines forming part of bridged ring systems
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- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Abstract
The invention discloses a huperzine A composition tablet and a preparation method thereof, belonging to the technical field of pharmaceutical preparations. The huperzine A tablet is prepared from huperzine A, a filling agent, a disintegrating agent, a lubricating agent and the like. The invention also provides a preparation method of the composition, which comprises the steps of dissolving huperzine A in 95% ethanol, uniformly mixing the diluent and the disintegrating agent, spraying the huperzine A ethanol solution, uniformly stirring, drying at 60 ℃, granulating, adding the lubricant, uniformly mixing and tabletting. The huperzine A tablet provided by the invention has the characteristics of uniform content, quick dissolution, good quality and stability and the like; the preparation method has simple steps and stable and reliable process, and can meet the requirement of large-scale production of the preparation.
Description
Technical Field
The invention belongs to the field of pharmacy, and relates to a huperzine A pharmaceutical composition and a preparation method thereof.
Background
Huperzine A (huperzine A, Hup A) is a huperzine alkaloid extracted and separated from huperzia serrata which is a perennial fern plant, is a strong reversible ChEIs, has stronger selective inhibition effect on acetylcholinesterase, and has the effect of promoting the learning and memory of mice. Is one of the only few drugs first discovered by chinese scientists. The Hup A has unique chemical structure, high oral bioavailability, easy blood brain barrier passing effect, multiple target point effect, long acting time, no tolerance after multiple times of administration and other features. Hup A is widely used in clinic at present, and a plurality of products are sold on the market, such as tablets, such as Harbourine and Shuangyiping, capsules, such as Fupexin, and injection, such as Rarisperidone. The therapeutic dosage of the huperzine A is extremely small, the huperzine A is generally taken once by 100-200 mug, the specification of a commercially available tablet is 50 mug, the weight of the tablet is about 60mg, and the main drug accounts for only 0.08 percent (wt) of the weight of the whole preparation, so that the problem of uneven content is easily caused during production. Huperzine A is unstable to light, dampness and heat, and has incompatibility with most adjuvants. We have found in the research that huperzine A oral solid preparation is very unstable and is easy to degrade. The related substances of the commercial oral tablets are detected, and the related substances are close to the limit of 4%. The increase of related substances in the huperzine A oral solid preparation can affect the treatment effect and even cause adverse reaction. Therefore, the stability of the effective components in the huperzine A oral solid preparation and the control of the quantity of related substances have important significance.
Chinese patent CN101721416B is to add pH regulator into the prescription to increase the stability of tablet, and accelerate the speed of 3 months to make the related substances less than 4%, but because of introducing dilute acid in the preparation, the method solves the problem of dissolving huperzine A and partial dispersion during production, but because of introducing dilute acid, the method causes corrosion to production equipment.
Chinese patent 200710093156.9 discloses freeze-drying method for preparing huperzine a lyophilized dispersion to improve stability of the preparation. However, the method only solves the problems that the adverse effect of damp and heat on the huperzine A is avoided in the production process, the influence of the huperzine A by illumination and the like is not fundamentally solved, and the incompatibility problem between the huperzine A and auxiliary materials is not solved; in addition, the freeze-drying method has high production cost, and the product cost is increased by adopting the method for production.
Chinese patent CN101991859 prepares huperzine A into beta-cyclodextrin inclusion compound to improve the stability of the preparation, but the factors influencing the inclusion process are more, and the problem of low inclusion rate exists, meanwhile, the cyclodextrin inclusion technology mostly stays in the research stage, is not suitable for the industrialized mass production, and has less practical application and related products.
Therefore, the problem of poor stability of the huperzine A tablet is not fundamentally solved in the prior art.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a pharmaceutical composition containing huperzine A.
The pharmaceutical composition has uniform content, rapid dissolution, and remarkably improved quality and stability; the preparation method has simple steps and stable and reliable process, and is suitable for large-scale industrial production.
The pharmaceutical composition provided by the invention comprises the following components in percentage by weight:
0.08-0.25% of huperzine A,
the diluent is 90-98 percent,
0 to 9 percent of disintegrating agent,
0.5 to 1 percent of lubricant,
wherein the diluent is selected from one or more of lactose, mannitol, anhydrous calcium hydrogen phosphate and dihydrate calcium hydrogen phosphate; preferably, the diluent is anhydrous calcium hydrogen phosphate.
Wherein the disintegrant is selected from one or more of crospovidone, sodium carboxymethyl starch and croscarmellose sodium; preferably, the disintegrant is sodium carboxymethyl starch.
The lubricant is selected from one or more of sodium stearyl fumarate and aerosil, and preferably, the lubricant is sodium stearyl fumarate.
Most preferably, the pharmaceutical composition of the present invention comprises the following components in percentage by weight:
0.08 percent of huperzine A,
97.96 percent of anhydrous calcium hydrophosphate,
1.47 percent of sodium carboxymethyl starch,
and 0.49 percent of sodium stearyl fumarate.
The pharmaceutical composition can be prepared into any pharmaceutically acceptable dosage form, preferably tablets.
It is another object of the present invention to provide a process for the preparation of the pharmaceutical composition of the present invention.
The preparation method comprises the following steps:
1) dissolving huperzine A in 70-99% ethanol at a ratio of huperzine A to ethanol of 0.5-2:50-200(W: V);
2) mixing anhydrous calcium hydrogen phosphate and carboxymethyl starch sodium uniformly, spraying huperzine-methyl ethanol solution obtained in step 1), stirring uniformly, drying, grading, adding lubricant, mixing uniformly, and tabletting.
Preferably, the preparation method of the invention comprises the following steps:
1) dissolving huperzine A in 95% ethanol at a ratio of huperzine A to 95% ethanol of 1:100(W: V);
2) mixing anhydrous calcium hydrogen phosphate and carboxymethyl starch sodium uniformly, spraying huperzine-methyl ethanol solution in 1), stirring uniformly, drying at 60 deg.C, grading with 60 mesh sieve, adding lubricant, mixing uniformly, and tabletting.
The invention has the beneficial effects that: the preparation method has the advantages of simple preparation process, improvement of production efficiency, reduction of production cost and suitability for industrial production. The obtained huperzine A tablet has good content uniformity and rapid dissolution, and provides guarantee for improving bioavailability. In addition, the prepared tablet has excellent stability, and the accelerated test result of 3 months shows that the related substances do not change obviously, so that the quality of the tablet is more stable and controllable, and the safety and the effectiveness of clinical medication are better ensured.
Detailed Description
The present invention is further illustrated by the following specific examples, which are not to be construed as limiting the invention thereto.
Example 1
Consists of the following components: huperzine A0.1 g, lactose 80g, sodium carboxymethyl starch 5g, sodium stearyl fumarate 0.08g, and 95% ethanol solution 15ml, and making into 1000 tablets.
The preparation method comprises the following steps: dissolving huperzine A in 95% ethanol; mixing lactose and sodium carboxymethyl starch uniformly, spraying huperzine-methyl ethanol solution, stirring uniformly, drying at 60 deg.C, granulating with 60 mesh sieve, adding sodium stearyl fumarate, mixing uniformly, and tabletting.
Example 2
Consists of the following components: huperzine A0.1 g, mannitol 80g, sodium carboxymethyl starch 5g, sodium stearyl fumarate 0.08g, and 95% ethanol solution 15ml, and making into 1000 tablets.
The preparation method comprises the following steps: dissolving huperzine A in 95% ethanol; mixing mannitol and sodium carboxymethyl starch uniformly, spraying huperzine-methyl ethanol solution, stirring uniformly, drying at 60 deg.C, granulating with 60 mesh sieve, adding sodium stearyl fumarate, mixing uniformly, and tabletting.
Example 3
Consists of the following components: huperzine A0.1 g, calcium hydrogen phosphate dihydrate 80g, sodium carboxymethyl starch 5g, sodium stearyl fumarate 0.08g, and 95% ethanol solution 15ml, and making into 1000 tablets.
The preparation method comprises the following steps: dissolving huperzine A in 95% ethanol; mixing calcium hydrogen phosphate dihydrate and sodium carboxymethyl starch uniformly, spraying huperzine-methyl ethanol solution, stirring uniformly, drying at 60 deg.C, granulating with 60 mesh sieve, adding sodium stearyl fumarate, mixing uniformly, and tabletting.
Example 4
Consists of the following components: huperzine A0.1 g, anhydrous calcium hydrogen phosphate 80g, sodium carboxymethyl starch 5g, sodium stearyl fumarate 0.08g, and 95% ethanol solution 15ml, and making into 1000 tablets.
The preparation method comprises the following steps: dissolving huperzine A in 95% ethanol; mixing anhydrous calcium hydrogen phosphate and carboxymethyl starch sodium, spraying huperzine-methyl ethanol solution, stirring, drying at 60 deg.C, grading with 60 mesh sieve, adding sodium stearyl fumarate, mixing, and tabletting.
Example 5
Consists of the following components: huperzine A0.1 g, anhydrous calcium hydrogen phosphate 120g, sodium carboxymethyl starch 1.8g, sodium stearyl fumarate 0.6g, and 95% ethanol solution 30ml, and making into 1000 tablets.
The preparation method comprises the following steps: dissolving huperzine A in 95% ethanol; mixing anhydrous calcium hydrogen phosphate and carboxymethyl starch sodium, spraying huperzine-methyl ethanol solution, stirring, drying at 60 deg.C, grading with 60 mesh sieve, adding sodium stearyl fumarate, mixing, and tabletting.
Example 6
Consists of the following components: huperzine A0.1 g, anhydrous calcium hydrogen phosphate 40g, sodium carboxymethyl starch 0.6g, sodium stearyl fumarate 0.2g, and 95% ethanol solution 30ml, and making into 1000 tablets.
The preparation method comprises the following steps: dissolving huperzine A in 95% ethanol; mixing anhydrous calcium hydrogen phosphate and carboxymethyl starch sodium, spraying huperzine-methyl ethanol solution, stirring, drying at 60 deg.C, grading with 60 mesh sieve, adding sodium stearyl fumarate, mixing, and tabletting.
Example 7
Consists of the following components: huperzine A0.1 g, anhydrous calcium hydrogen phosphate 40g, sodium carboxymethyl starch 4.0g, sodium stearyl fumarate 0.2g, and 95% ethanol solution 15ml, and making into 1000 tablets.
The preparation method comprises the following steps: dissolving huperzine A in 95% ethanol; mixing anhydrous calcium hydrogen phosphate and carboxymethyl starch sodium, spraying huperzine-methyl ethanol solution, stirring, drying at 60 deg.C, grading with 60 mesh sieve, adding sodium stearyl fumarate, mixing, and tabletting.
Example 8
Consists of the following components: huperzine A0.1 g, anhydrous calcium hydrogen phosphate 100g, sodium carboxymethyl starch 5.0g, sodium stearyl fumarate 1.0g, silica gel micropowder 1.0g, and 95% ethanol solution 15ml, and making into 1000 tablets.
The preparation method comprises the following steps: dissolving huperzine A in 95% ethanol; mixing anhydrous calcium hydrogen phosphate and carboxymethyl starch sodium, spraying huperzine-methyl ethanol solution, stirring, drying at 60 deg.C, grading with 60 mesh sieve, adding sodium stearyl fumarate and silica gel micropowder, mixing, and tabletting.
Example 9
Consists of the following components: huperzine A0.1 g, anhydrous calcium hydrogen phosphate 100g, crosslinked PVP 7.5g, sodium stearyl fumarate 1.0g, 95% ethanol solution 15ml, and making into 1000 tablets.
The preparation method comprises the following steps: dissolving huperzine A in 95% ethanol; mixing anhydrous calcium hydrogen phosphate and cross-linked PVP uniformly, spraying huperzine-methyl ethanol solution, stirring uniformly, drying at 60 deg.C, grading with 60 mesh sieve, adding sodium stearyl fumarate, mixing uniformly, and tabletting.
Example 10
Consists of the following components: huperzine A0.1 g, anhydrous calcium hydrogen phosphate 100g, croscarmellose sodium 7.5g, sodium stearyl fumarate 1.0g, and 95% ethanol solution 15ml, and making into 1000 tablets.
The preparation method comprises the following steps: dissolving huperzine A in 95% ethanol; mixing anhydrous calcium hydrogen phosphate and croscarmellose sodium, spraying huperzine-methyl ethanol solution, stirring, drying at 60 deg.C, grading with 60 mesh sieve, adding sodium stearyl fumarate, mixing, and tabletting.
EXAMPLE 11 content uniformity determination
The a +2.2S values were calculated according to the content uniformity measurement method (0941, the four general rules of chinese pharmacopoeia 2015), taking the tablets obtained in example 5, example 6 and example 8, and the results are shown in the following table:
| example 5 | Example 6 | Example 8 | |
| 1 | 101.5 | 98.9 | 98.8 |
| 2 | 99.4 | 97.8 | 99.0 |
| 3 | 99.1 | 99.4 | 100.5 |
| 4 | 99.7 | 100.7 | 98.6 |
| 5 | 100.4 | 101.8 | 98.6 |
| 6 | 100.1 | 100.6 | 102.6 |
| 7 | 99.8 | 101.4 | 103.0 |
| 8 | 99.9 | 100.9 | 101.7 |
| 9 | 98.7 | 99.5 | 101.7 |
| 10 | 98.1 | 101.2 | 99.6 |
| Mean value of | 99.7 | 100.2 | 100.4 |
| S | 0.94 | 1.27 | 1.73 |
| A+2.2S | 2.2 | 3.0 | 4.2 |
The result shows that the A +2.2S values of the content uniformity of the tablets in the embodiment of the invention measured by a content uniformity inspection method are all less than 15, which shows that the content uniformity of the tablets prepared by the preparation method disclosed by the invention is good. Example 5 is clearly superior to the other examples.
EXAMPLE 12 dissolution test methods and results
According to the apparatus of the second method of dissolution and release rate measurement (0931 of the four general guidelines of the chinese pharmacopoeia 2015 edition), samples prepared in examples 1, 2, 4, 5, 6, 7 and 8 were taken, and 2ml of each of 5, 10, 15 and 30min was sampled and filtered according to the method using 500ml of buffer solution with ph6.8 as dissolution medium and 50rpm as rotation speed, and the filtrate was measured. Taking a proper amount of reference substances, and calculating the release degree according to an external standard method. The results of the experiments are shown in the following table:
the result shows that the prepared huperzine A tablet is dissolved out quickly, and the release rate in 15min is over 85 percent. In comparison, the dissolution effect of example 5 is superior to that of the other examples.
Example 13 stability test
The tablets obtained in examples 5, 6 and 8 and commercially available tablets (huperzine A tablets, trade name: Haberein; manufacturer: Henan Tailong pharmaceutical Co., Ltd.; batch No. 141010) were taken and placed under accelerated test conditions (temperature 40 ℃, relative humidity 75% environment, aluminum-plastic packaging) according to the stability test guidelines of the four parts 9001 of the bulk drugs and pharmaceutical preparations in the pharmacopoeia 2015 edition, influencing factor conditions (high temperature: 60 ℃ C., 10 d; high humidity: 92.5%, 10 d; light 4500lux,10 d). The relevant substances of the tablets are examined. The results are shown in the following table:
the above experimental results show that: compared with the commercially available tablet, the tablet obtained by the invention is more resistant to the effects of high temperature, high humidity and light, and the total impurities are less than 1 percent. After the tablet is placed for 3 months through an accelerated test, the growth of related substances is not obvious (less than 0.2%), the stability is good, and the tablet is obviously improved compared with a commercially available tablet. Example 5 is significantly better in stability than the other examples.
Claims (3)
1. A tablet containing huperzine A is characterized by comprising the following components in percentage by weight:
0.08 percent of huperzine A,
97.96 percent of anhydrous calcium hydrophosphate,
1.47 percent of sodium carboxymethyl starch,
and 0.49 percent of sodium stearyl fumarate.
2. A process for preparing a tablet according to claim 1, comprising the steps of:
1) dissolving huperzine A in 70-99% ethanol at a ratio of huperzine A to ethanol of 0.5-2:50-200(W: V);
2) mixing anhydrous calcium hydrogen phosphate and carboxymethyl starch sodium, spraying into huperzine-methyl ethanol solution of 1), stirring, drying, grading, adding sodium stearyl fumarate, mixing, and tabletting.
3. A process for preparing a tablet according to claim 1, comprising the steps of:
1) dissolving huperzine A in 95% ethanol at a ratio of huperzine A to 95% ethanol of 1:100(W: V);
2) mixing anhydrous calcium hydrogen phosphate and carboxymethyl starch sodium uniformly, spraying huperzine-methyl ethanol solution in 1), stirring uniformly, drying at 60 deg.C, grading with 60 mesh sieve, adding sodium stearyl fumarate, mixing uniformly, and tabletting.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1568985A (en) * | 2003-07-21 | 2005-01-26 | 北京小伙伴医药生物技术有限公司 | Orally disintegrating tablet of Huperzine A and its preparation |
| CN104352467A (en) * | 2014-11-17 | 2015-02-18 | 辰欣药业股份有限公司 | Huperzine A tablet and preparation method thereof |
| US20170326163A1 (en) * | 2013-03-13 | 2017-11-16 | Genetic Disease Investigators, LLC | Methods and compositions for treatment of dry eye and correction of organ dysfunctions |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1568985A (en) * | 2003-07-21 | 2005-01-26 | 北京小伙伴医药生物技术有限公司 | Orally disintegrating tablet of Huperzine A and its preparation |
| US20170326163A1 (en) * | 2013-03-13 | 2017-11-16 | Genetic Disease Investigators, LLC | Methods and compositions for treatment of dry eye and correction of organ dysfunctions |
| CN104352467A (en) * | 2014-11-17 | 2015-02-18 | 辰欣药业股份有限公司 | Huperzine A tablet and preparation method thereof |
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