CN113440489A - Perampanel tablet and preparation method thereof - Google Patents
Perampanel tablet and preparation method thereof Download PDFInfo
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- CN113440489A CN113440489A CN202010226326.1A CN202010226326A CN113440489A CN 113440489 A CN113440489 A CN 113440489A CN 202010226326 A CN202010226326 A CN 202010226326A CN 113440489 A CN113440489 A CN 113440489A
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- perampanel
- polyethylene glycol
- tablet
- copovidone
- filler
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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
- A61K9/20—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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
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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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- 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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- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
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Abstract
The invention provides a Perampanel tablet and a preparation method thereof, wherein the prescription contains Perampanel, polyethylene glycol, copovidone, a filler, a disintegrating agent and a lubricant. The method melts the perampanel and the polyethylene glycol, then adds the melted perampanel and the polyethylene glycol into the ethanol solution of the copovidone, and then adds the corresponding filler, the disintegrant and the lubricant for tabletting, so that the dissolution effect of the prepared perampanel tablet is remarkably improved, the dissolution can reach more than 80% in 10min, the long-term storage stability is good, the preparation process is simple, no complex equipment is needed, and the industrial mass production is easy.
Description
Technical Field
The invention relates to a Perampanel tablet and a preparation method thereof, the preparation method is simple and controllable, and the prepared tablet has high dissolution rate, quick response and stable curative effect, and belongs to the technical field of medicines.
Background
Perampanel is an alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist that reduces neuronal hyperexcitability by inhibiting postsynaptic AMPA receptor glutamate activity. Perampanel is a popular antiepileptic drug because many patients with partial seizures cannot be effectively controlled by other therapeutic methods; current first-line antiepileptic drugs act by inhibiting the postsynaptic glutamate AMPA receptor, which is currently thought to be involved in seizures. Clinical trial results show that patients taking Perampanel have better control of seizures than patients taking placebo. This is the first FDA-approved antiepileptic drug with this mechanism of action; based on the above situation, the invention discloses a perampanel tablet prepared by direct powder compression or dry granulation compression, the preparation process is simple and controllable, the operability is high, the tablet is suitable for large-scale production, the prepared perampanel tablet has excellent appearance, the content and the dissolution rate are qualified, the taking compliance of patients is not influenced, the effect is fast, and the curative effect is stable.
Disclosure of Invention
The invention provides the Perampanel tablet which is good in stability, high in dissolution rate and simple in preparation process through the selection of auxiliary materials and the optimization of the preparation process. Specifically, the present invention is realized by the following technique.
A Perampanel tablet is composed of Perampanel, polyethylene glycol, copovidone and pharmaceutically acceptable auxiliary materials, wherein the pharmaceutically acceptable auxiliary materials comprise a filling agent, a disintegrating agent and a lubricating agent.
The Perampanel tablet comprises the following components in parts by weight:
perampanel 1 part
6-9 parts of copovidone
0.5-2 parts of polyethylene glycol
5-10 parts of filler
0.5-2 parts of disintegrating agent
0.1 to 0.5 portion of lubricant
Preferably, the weight ratio of the Perampanel to the polyethylene glycol is 1:1 in the Perampanel tablet. Preferably, the weight ratio of the perampanel to the copovidone is 1:7 in the perampanel tablet.
The Perampanel tablet is characterized in that the filler is one or more selected from lactose, microcrystalline cellulose, starch, pregelatinized starch, dextrin, mannitol, glucose, sorbitol, sucrose, calcium carbonate, calcium sulfate, calcium hydrogen phosphate, calcium phosphate and hydroxypropyl methyl cellulose, and is preferably microcrystalline cellulose.
The above-mentioned Perampanel tablet, the disintegrant is selected from one or more of crospovidone, croscarmellose sodium, cellulose acetate phthalate, low substituted hydroxypropyl cellulose and sodium carboxymethyl starch, preferably crospovidone.
The Perampanel tablet is characterized in that the lubricant is one or more selected from magnesium stearate, silicon dioxide, superfine silica gel powder, calcium stearate and sodium stearate fumarate, and is preferably magnesium stearate.
The invention also provides a preparation process for the Perampanel tablet, which comprises the following steps:
1) heating and melting the Perampanel and the polyethylene glycol, adding the molten liquid into an ethanol solution of copovidone according to the formula amount, and uniformly stirring for later use, wherein the melting temperature is 80 ℃;
2) sieving the filler and the disintegrant with a 80-mesh sieve for later use;
3) mixing the suspension obtained in step 1) with the filler and disintegrant obtained in step 2), stirring, drying at 50 deg.C or below, adding lubricant, mixing, and tabletting.
Compared with the prior art, the Perampanel tablet and the preparation process thereof have the following advantages and remarkable step:
(1) the Perampanel tablet prepared by the invention has the advantages that the Perampanel and the polyethylene glycol are heated and melted and added into the ethanol solution with the carrier dispersed, and the dissolution effect is obviously improved.
(2) The Perampanel tablet prepared by the prescription has high stability and is suitable for long-term storage.
(3) The preparation process provided by the invention is simple, does not need complex preparation equipment, and is easy for industrial mass production.
Detailed Description
The preparation and the effect of the present invention will be further described by the following examples, but the scope of the present invention is not limited to the following examples.
Example 1:
prescription of 1000 tablets:
perampanel 50g
Polyethylene glycol 50g
Pyvidone 350g
Microcrystalline cellulose 350g
Cross-linked Povidone 25g
Magnesium stearate 5g
1000g of ethanol
The preparation process comprises the following steps: (1) melting Perampanel and polyethylene glycol at 80 deg.C, adding the molten solution into ethanol solution of copovidone, and stirring
(2) Sieving crospovidone and microcrystalline cellulose with 80 mesh sieve respectively;
(3) adding the auxiliary materials in the step (2) into the auxiliary materials in the step (1), uniformly stirring, drying at the temperature of below 50 ℃, adding magnesium stearate, uniformly mixing and tabletting.
Example 2
Prescription of 1000 tablets:
perampanel 50g
Polyethylene glycol 50g
Copovidone 300g
Sorbitol 350g
Cross-linked Povidone 25g
Magnesium stearate 5g
1000g of ethanol
The preparation process is the same as in example 1.
Example 3:
prescription of 1000 tablets:
perampanel 50g
Polyethylene glycol 50g
Copovidone 450g
Microcrystalline cellulose 350g
Sodium carboxymethyl starch 25g
Magnesium stearate 5g
1000g of ethanol
The preparation process is the same as in example 1.
Example 4:
prescription of 1000 tablets:
perampanel 50g
Polyethylene glycol 25g
Pyvidone 350g
Microcrystalline cellulose 350g
Cross-linked Povidone 25g
Magnesium stearate 5g
1000g of ethanol
The preparation process is the same as in example 1.
Example 5:
prescription of 1000 tablets:
perampanel 50g
Polyethylene glycol 100g
Pyvidone 350g
Microcrystalline cellulose 350g
Cross-linked Povidone 25g
Magnesium stearate 5g
1000g of ethanol
The preparation process is the same as in example 1.
Comparative example 1:
prescription of 1000 tablets:
perampanel 50g
Polyethylene glycol 100g
Co-polyvidone 250g
Microcrystalline cellulose 350g
Cross-linked Povidone 25g
Magnesium stearate 5g
1000g of ethanol
The preparation process is the same as in example 1.
Comparative example 2:
prescription of 1000 tablets:
perampanel 50g
Polyethylene glycol 150g
Co-polyvidone 250g
Microcrystalline cellulose 350g
Cross-linked Povidone 25g
Magnesium stearate 5g
1000g of ethanol
The preparation process is the same as in example 1.
Comparative example 3:
prescription of 1000 tablets:
perampanel 50g
Pyvidone 350g
Microcrystalline cellulose 350g
Cross-linked Povidone 25g
Magnesium stearate 5g
1000g of ethanol
The preparation process comprises the following steps:
(1) melting Perampanel by heating at 120 ℃, adding into an ethanol solution of copovidone in a formula amount, and uniformly stirring for later use;
(2) sieving crospovidone and microcrystalline cellulose with 80 mesh sieve respectively;
(3) adding the auxiliary materials in the step (2) into the auxiliary materials in the step (1), uniformly stirring, drying at the temperature of below 50 ℃, adding magnesium stearate, uniformly mixing and tabletting.
Comparative example 4
The prescription composition is as follows:
perampanel 10g
35g of copovidone
Microcrystalline cellulose 42.5g
L-HPC (Internally) 4g
L-HPC (plus) 4g
Magnesium stearate 1g
The preparation method comprises the following steps:
weighing and uniformly mixing the formula amount of Perampanel, mannitol, microcrystalline cellulose and L-HPC, weighing polyvinylpyrrolidone to prepare an aqueous solution serving as an adhesive for granulation, adding the rest L-HPC, adding magnesium stearate, mixing and tabletting to obtain the finished product.
Comparative example 5:
prescription of 1000 tablets:
perampanel 50g
Polyethylene glycol 50g
Pyvidone 350g
Microcrystalline cellulose 350g
Cross-linked Povidone 25g
Magnesium stearate 5g
1000g of ethanol
The preparation process comprises the following steps:
(1) respectively sieving the perampanel, the crospovidone and the microcrystalline cellulose by a sieve of 80 meshes for later use;
(2) adding the mixture obtained in the step (1) and polyethylene glycol into the ethanol solution of copovidone according to the formula amount, uniformly stirring for later use, drying at the temperature of below 50 ℃, adding magnesium stearate, uniformly mixing and tabletting.
Verification of the examples:
and (3) dissolution rate determination: taking the product at the dissolution rate, taking 900mL of 0.lmol/L hydrochloric acid solution as a dissolution medium according to a dissolution determination method 2015 (appendix XC second method), rotating at 50 revolutions per minute, operating according to the method, taking a proper amount of solution after 10min, 20min and 30min respectively, filtering, precisely taking 5mL of subsequent filtrate, placing the subsequent filtrate in a 25mL measuring flask, diluting the subsequent filtrate to a scale with 0.lmol/L hydrochloric acid solution, shaking uniformly, and determining absorbance at a wavelength of 254mn according to an ultraviolet-visible spectrophotometry (appendix IVA); the amount of elution was calculated for each tablet. Taking a proper amount of Perampanel reference substance, precisely weighing, adding 0.lmol/L hydrochloric acid solution for dissolving, quantitatively diluting to prepare a solution containing about L0 mu g of Perlml, measuring by the same method, and calculating the dissolution amount of each tablet. The limit is 80% of the indicated amount and should be met. The results are shown in Table 1.
And (3) related substance determination: taking a proper amount of the fine powder of the product, adding a mobile phase for dissolving and diluting to prepare a solution containing about 0.5mg of Perampanel in each lml, filtering, and taking a subsequent filtrate as a test solution; precisely measure 1ml, place in a 100ml measuring flask, dilute to the scale with mobile phase, shake well, as control solution. According to the test of high performance liquid chromatography (appendix V D), octadecylsilane chemically bonded silica is used as a filler, methanol-water (70: 30) is used as a mobile phase, the detection wavelength is 221mn, and the number of theoretical plates is not less than 2000 in terms of Perampanel peak. Taking l0 mu l of contrast solution to be injected into a liquid chromatograph, adjusting the detection sensitivity to enable the peak height of the main component chromatographic peak to be about 20% of the full range, precisely measuring l0 mu l of the test solution and the contrast solution, respectively injecting the test solution and the contrast solution into the liquid chromatograph, recording the chromatogram until the retention time of the main component chromatographic peak is 3 times, wherein if an impurity peak exists in the chromatogram of the test solution, the peak area of a single impurity is not more than 0.5 time (0.5%) of the main peak area of the contrast solution, and the sum of the peak areas of the impurities is not more than the area (1.0%) of the main peak of the contrast solution. The results are shown in Table 1.
The accelerated test conditions were: the samples of the examples and comparative examples were placed in a stability testing cabinet at a temperature of 40 ℃. + -. 2 ℃ and a relative humidity of 75%. + -. 5%, and the accelerated stability was examined for 3 months, and the dissolution rates and related substances were measured by the above-described method. The results are shown in Table 2.
TABLE 1 dissolution rates and related substances for each group
As can be seen from table 1: the dissolution rate of the example group is more than 80% within 10min, and particularly the dissolution rate of the example 1 is 99.5% within 10 min. Comparative example 1 has a low content of solubilizer and a poor dissolution effect. Comparative example 2 higher levels of solubilizing agents, such as polyethylene glycol, were found to have sticking problems during tableting. Comparative example 3 no polyethylene glycol was used, which had a great effect on the dissolution of the Perampanel tablets. Comparative example 4 also failed to achieve the technical effects of the present invention by a different method. Comparative example 5 both the formulation and the preparation method are different from the present invention, and the dissolution rate of the perampanel tablet is significantly reduced.
TABLE 2 dissolution rates and related substances for each group after accelerated testing
As can be seen from Table 2, after the accelerated test, the dissolution rate and the content of the related substances of the example groups did not change significantly, and the related substances increased slowly. The content of related substances in the comparative examples is obviously increased, and the dissolution rate is also obviously reduced, particularly the content of the total impurities in the comparative examples 2, 3 and 4 is more than 1 percent.
Finally, the above embodiments are only for illustrating the technical solutions of the present invention and not for limiting, although the present invention has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions may be made to the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention, and all of them should be covered in the claims of the present invention.
Claims (5)
1. The Perampanel tablet is characterized by consisting of Perampanel, polyethylene glycol, copovidone and pharmaceutically acceptable auxiliary materials, wherein the pharmaceutically acceptable auxiliary materials comprise a filling agent, a disintegrating agent and a lubricating agent, and the components are calculated according to the weight ratio as follows:
perampanel 1 part
6-9 parts of copovidone
0.5-2 parts of polyethylene glycol
5-10 parts of filler
0.5-2 parts of disintegrating agent
0.1 to 0.5 portion of lubricant
Wherein the filler is selected from one or more of lactose, microcrystalline cellulose, starch, pregelatinized starch, dextrin, mannitol, glucose, sorbitol, sucrose, calcium carbonate, calcium sulfate, calcium hydrogen phosphate, calcium phosphate, and hydroxypropyl methylcellulose; the disintegrant is selected from one or more of crospovidone, croscarmellose sodium, cellulose acetate phthalate, low-substituted hydroxypropyl cellulose and sodium carboxymethyl starch; the lubricant is selected from one or more of magnesium stearate, silicon dioxide, superfine silica gel powder, calcium stearate and sodium stearate fumarate; the Perampanel tablet is prepared by the following method:
1) heating and melting the Perampanel and the polyethylene glycol, adding the molten liquid into an ethanol solution of copovidone according to the formula amount, and uniformly stirring for later use, wherein the heating and melting temperature is 80 ℃;
2) sieving the filler and the disintegrant with a 80-mesh sieve for later use;
3) mixing the suspension obtained in step 1) with the filler and disintegrant obtained in step 2), stirring, drying at 50 deg.C below, adding lubricant, mixing, and tabletting.
2. The perampanel tablet according to claim 1, wherein the weight ratio of the perampanel to the polyethylene glycol is 1: 0.5-1.
3. The perampanel tablet according to claim 1, wherein the weight-to-weight ratio of perampanel to copovidone is 1: 6-7.
4. The perampanel tablet according to claim 1, wherein the weight ratio of the perampanel, the polyethylene glycol and the copovidone is 1: 1: .
5. Perampanel tablet according to claim 1, wherein the filler is microcrystalline cellulose and the disintegrant is crospovidone; the lubricant is magnesium stearate.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010226326.1A CN113440489A (en) | 2020-03-27 | 2020-03-27 | Perampanel tablet and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010226326.1A CN113440489A (en) | 2020-03-27 | 2020-03-27 | Perampanel tablet and preparation method thereof |
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| Publication Number | Publication Date |
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| CN113440489A true CN113440489A (en) | 2021-09-28 |
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| CN202010226326.1A Pending CN113440489A (en) | 2020-03-27 | 2020-03-27 | Perampanel tablet and preparation method thereof |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113984944A (en) * | 2021-11-15 | 2022-01-28 | 南京华威医药科技集团有限公司 | Detection method of Perampanel genotoxic impurities |
| CN118319870A (en) * | 2024-04-15 | 2024-07-12 | 中日友好医院(中日友好临床医学研究所) | Non-netilone tablet and preparation method thereof |
-
2020
- 2020-03-27 CN CN202010226326.1A patent/CN113440489A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113984944A (en) * | 2021-11-15 | 2022-01-28 | 南京华威医药科技集团有限公司 | Detection method of Perampanel genotoxic impurities |
| CN118319870A (en) * | 2024-04-15 | 2024-07-12 | 中日友好医院(中日友好临床医学研究所) | Non-netilone tablet and preparation method thereof |
| CN118319870B (en) * | 2024-04-15 | 2024-09-17 | 中日友好医院(中日友好临床医学研究所) | Non-netilone tablet and preparation method thereof |
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