CN115590830A - Broglitazone sustained-release preparation and preparation method thereof - Google Patents
Broglitazone sustained-release preparation and preparation method thereof Download PDFInfo
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- CN115590830A CN115590830A CN202110773353.5A CN202110773353A CN115590830A CN 115590830 A CN115590830 A CN 115590830A CN 202110773353 A CN202110773353 A CN 202110773353A CN 115590830 A CN115590830 A CN 115590830A
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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
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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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
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- A—HUMAN NECESSITIES
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- A61K9/2013—Organic compounds, e.g. phospholipids, fats
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
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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 discloses a brivaracetam sustained-release preparation and a preparation method thereof. The brivaracetam sustained-release preparation comprises an active pharmaceutical ingredient, an ionic framework sustained-release material and a neutral framework sustained-release material, wherein the active pharmaceutical ingredient is brivaracetam, one or more of brivaracetam pharmaceutically acceptable complexes, salts, solvates and hydrates thereof. The sustained-release brivaracetam preparation can ensure that the release of the preparation keeps a certain rule, reduces the food effect, has high safety, is not influenced by the internal environment of a receptor and an external force, and has the advantages of simple preparation process, short production period, low cost and easy production and amplification.
Description
Technical Field
The invention relates to a brivaracetam sustained-release preparation and a preparation method thereof.
Background
International patent application publication No. WO 01/62726 discloses 2-oxo-1-pyrrolidine derivatives and a process for their preparation, which discloses the compound (2S) -2- [ (4R) -2-oxo-4-propyl-pyrrolidin-1-yl ] butanamide, under the international non-proprietary name brivaracetam, of the formula:
brivaracetam is a novel high-affinity ligand of SV2A in presynaptic nerve terminal, and has wide antiepileptic activity and higher safety. European drug administration (EMA) and the U.S. Food and Drug Administration (FDA) approved treatments for partial seizure type epilepsy at age 16 and above with or without adjunctive therapy for secondary generalized seizures in 2016 (1-month and 14-year) and 2016 (2-month and 18-day), respectively, under the trade names of
The medicine is a derivative of levetiracetam, belongs to 3 rd generation antiepileptic medicines, has affinity 15-30 times that of levetiracetam, and can reduce dosage by about 10 times.
Currently marketed brivaracetam oral tablets (size: 10, 25, 50, 75, 100 mg) are immediate release formulations, with a recommended starting dose of 50mg 2 times daily, which may be adjusted down to 25mg 2 times daily or to 100mg 2 times daily, depending on individual patient tolerance and therapeutic response, all requiring multiple administrations. By preparing the sustained release preparation, the daily administration times can be reduced, and the compliance of patients can be improved.
Patent CN202010262862.7 discloses a preparation method of a brivaracetam controlled release preparation, which achieves an in vitro zero-order constant-speed drug release curve, and adopts a single-chamber osmotic pump and laser drilling technology, wherein a tablet core is coated with a semi-permeable membrane coating, and then a drug release pore is drilled on the coating membrane by using a laser means, so that the preparation process is complex, the production period is long, the cost is high, the requirement on drilling precision is high, and differences are easily caused; patent CN200980120221.X provides a prolonged release preparation containing brivaracetam, adopts hydroxypropyl methylcellulose as a hydrophilic gel skeleton to achieve a sustained release dissolution effect, but a single hydroxypropyl methylcellulose skeleton sustained release system is easily affected by the in vivo environment, has a strong food effect, and may cause in vivo burst release to influence the safety, and the patent does not evaluate the in vivo effect.
Disclosure of Invention
The invention provides a brivaracetam sustained-release preparation and a preparation method thereof, aiming at overcoming the defects that the existing brivaracetam needs to be taken for multiple times, the preparation difficulty of the sustained-release preparation is high, the food effect is obvious and the like. The brivaracetam sustained-release preparation can prolong the in-vivo drug release time and achieve the effect of once-a-day oral administration by controlling the release rate; has less food effect; the preparation process is simple, the production period is short, the cost is low, and the production amplification is easy.
The common skeleton sustained-release tablet has stronger food effect, and the main reasons are as follows: 1. the release of the matrix tablet is influenced by the pH of the environment, and the change of the pH of the gastrointestinal tract before and after eating is easy to cause the change of the release rate; 2. after eating, the food extrusion and gastrointestinal peristalsis are enhanced, and the matrix tablet is released quickly under the action of external force. The invention discovers that when the tablet core contains the ionic skeleton slow release material, the release curves of the slow release tablet keep the same rule: the drug is released most quickly in hydrochloric acid solution (simulating gastric acid environment under the condition of no eating) with pH1.2, and is released more slowly and with a release curve similar to that of phosphate buffer solution (simulating intestinal tract environment after eating) with pH4.5 and pH6.8, namely, the drug is released more quickly in gastrointestinal tract environment before eating and is released more slowly in gastrointestinal tract environment after eating, so that the risk of in vivo burst release after eating is reduced, and the food effect is reduced.
The invention provides a brivaracetam sustained-release preparation, which comprises the following components: the active drug component comprises brivaracetam, a brivaracetam pharmaceutically acceptable complex, salt, solvate and hydrate thereof, or a combination of brivaracetam and brivaracetam pharmaceutically acceptable complex.
The sustained-release preparation of brivaracetam further preferably comprises a filler and a lubricant.
The brivaracetam sustained-release preparation preferably comprises an active pharmaceutical ingredient, an ionic framework sustained-release material, a neutral framework sustained-release material, a filler and a lubricant, wherein the active pharmaceutical ingredient is brivaracetam, one or more of brivaracetam pharmaceutically acceptable complexes, salts, solvates and hydrates thereof.
The active pharmaceutical ingredient is preferably brivaracetam.
The amount of the active pharmaceutical ingredient is preferably 10.00% to 33.33%, for example 14.29%, 16.67% or 20.00%, the percentages being by weight of the active pharmaceutical ingredient relative to the total weight of the formulation composition.
The ionic type skeleton slow-release material is preferably one or more of sodium carboxymethylcellulose, carbomer, alginate, arabic gum, xanthan gum, acrylic acid polymer and methacrylic acid copolymer, and more preferably sodium carboxymethylcellulose and/or carbomer.
The amount of the ionic matrix slow-release material is preferably 2.00% -45.00%, such as 5.00%, 10.00%, 12.50%, 15.00%, 17.50%, 20.00% or 30.00%, wherein the percentage refers to the weight of the ionic matrix slow-release material to the total weight of the preparation composition.
The neutral skeleton slow release material is preferably one or more of a hydrophilic gel skeleton material, a waxy material and an insoluble skeleton material.
The hydrophilic gel framework material is preferably one or more of hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose and polyoxyethylene, and more preferably hydroxypropyl cellulose, hydroxypropyl methyl cellulose or hydroxyethyl cellulose.
The waxy material is preferably one or more of glyceryl behenate, stearic acid, stearyl alcohol, hydrogenated castor oil, carnauba wax and paraffin, and more preferably glyceryl behenate.
The insoluble framework material is preferably one or more of ethyl cellulose, polyacrylic resin, polyvinyl acetate povidone mixture, ethylene-vinyl acetate copolymer and cellulose acetate, and more preferably ethyl cellulose and/or polyvinyl acetate povidone mixture.
The dosage of the neutral skeleton slow release material is preferably 5.00-50.00%, more preferably 15.00-45.00%, such as 17.50%, 30.00%, 35.00% or 40.00%, and the percentage refers to the weight of the neutral skeleton slow release material in the total weight of the preparation composition.
The filler is preferably one or more of lactose, microcrystalline cellulose, silicified microcrystalline cellulose, mannitol, pregelatinized starch, sucrose, calcium hydrogen phosphate, starch and dextrin, and more preferably lactose.
The filler is preferably used in an amount of 2.33% to 65.33%, e.g., 10.67%, 16.83%, 29.00%, 36.33%, 37.33%, 45.33%, 49.71%, 54.71%, or 64.00% by weight of filler to the total weight of the formulation composition.
The lubricant is preferably one or more of magnesium stearate, talcum powder, colloidal silicon dioxide and calcium stearate, and is more preferably magnesium stearate.
The lubricant is generally used in an amount to make up the balance to 100.00%, preferably 1.00% to 3.00%, for example 1.50% or 2.00%, the percentages being by weight of lubricant to the total weight of the formulation composition.
The dosage form of the sustained-release preparation of brivaracetam of the present invention is preferably a tablet, and the tablet weight is preferably 300mg to 1000mg, such as 700mg, 600mg or 500mg.
The brivaracetam sustained release preparation of the present invention is preferably administered orally, and the dose thereof is preferably administered once a day. The sustained-release preparation provided by the invention preferably comprises the following components in percentage by weight:
the percentage is the ratio of the weight of each component to the total weight of the preparation composition.
The sustained release preparation provided by the invention preferably comprises the following components in percentage by weight:
the percentage is the ratio of the weight of each component relative to the total weight of the preparation composition.
The sustained release preparation provided by the invention preferably comprises the following components in percentage by weight:
the percentage is the ratio of the weight of each component relative to the total weight of the preparation composition.
In a preferred embodiment of the present invention, the brivaracetam sustained release agent is a formula 1, and the formula 1 comprises the following components by weight:
the percentage is the ratio of the weight of each component relative to the total weight of the preparation composition.
In a preferred embodiment of the present invention, the brivaracetam sustained release agent is a formula 2, and the formula 2 comprises the following components by weight:
the percentage is the ratio of the weight of each component relative to the total weight of the preparation composition.
In a preferred embodiment of the present invention, the brivaracetam sustained release agent is a formula 3, and the formula 3 comprises the following components by weight:
the percentage is the ratio of the weight of each component relative to the total weight of the preparation composition.
In a preferred embodiment of the present invention, the brivaracetam sustained release agent is a formula 4, and the formula 4 comprises the following components by weight:
the percentage is the ratio of the weight of each component to the total weight of the preparation composition.
In a preferred embodiment of the present invention, the brivaracetam sustained release agent is a formula 5, and the formula 5 comprises the following components by weight:
the percentage is the ratio of the weight of each component to the total weight of the preparation composition.
In a preferred embodiment of the present invention, the brivaracetam sustained release agent is a formula 6, and the formula 6 comprises the following components by weight:
the percentage is the ratio of the weight of each component relative to the total weight of the preparation composition.
In a preferred embodiment of the present invention, the brivaracetam sustained release agent is a formula 7, and the formula 7 comprises the following components by weight:
the percentage is the ratio of the weight of each component relative to the total weight of the preparation composition.
In a preferred embodiment of the present invention, the brivaracetam sustained release agent is a formula 8, and the formula 8 comprises the following components by weight:
the percentage is the ratio of the weight of each component relative to the total weight of the preparation composition.
In a preferred embodiment of the present invention, the brivaracetam sustained release agent is a formula 9, and the formula 9 comprises the following components by weight:
the percentage is the ratio of the weight of each component relative to the total weight of the preparation composition.
In a preferred embodiment of the present invention, the brivaracetam sustained release formulation is a formulation 10, and the formulation 10 comprises the following components by weight:
the percentage is the ratio of the weight of each component relative to the total weight of the preparation composition.
In a preferred embodiment of the present invention, the brivaracetam sustained release formulation is a formulation 11, and the formulation 11 comprises the following components by weight:
the percentage is the ratio of the weight of each component to the total weight of the preparation composition.
In a preferred embodiment of the present invention, the brivaracetam sustained release formulation is a formulation 12, and the formulation 12 comprises the following components by weight:
the percentage is the ratio of the weight of each component to the total weight of the preparation composition.
In a preferred embodiment of the present invention, the brivaracetam sustained release formulation is a formulation 13, and the formulation 13 comprises the following components by weight:
the percentage is the ratio of the weight of each component relative to the total weight of the preparation composition.
In a preferred embodiment of the present invention, the brivaracetam sustained release agent is a formula 14, and the formula 14 comprises the following components by weight:
the percentage is the ratio of the weight of each component relative to the total weight of the preparation composition.
In a preferred embodiment of the present invention, the brivaracetam sustained release agent is a formula 15, and the formula 15 comprises the following components by weight:
the percentage is the ratio of the weight of each component relative to the total weight of the preparation composition.
In a preferred embodiment of the present invention, the brivaracetam sustained release preparation is a formula 16, and the formula 16 comprises the following components by weight:
the percentage is the ratio of the weight of each component relative to the total weight of the preparation composition.
In a preferred embodiment of the present invention, the brivaracetam sustained release agent is a formula 17, and the formula 17 comprises the following components by weight:
the percentage is the ratio of the weight of each component relative to the total weight of the preparation composition.
The weight of the brivaracetam sustained release preparation tablet prepared from the formula 1 to the formula 8 is preferably 700mg.
The weight of the brivaracetam sustained release tablets prepared by the formulas 9 to 14 is preferably 600mg.
The weight of the brivaracetam sustained release preparation tablet prepared by the formula 15 is preferably 300mg.
The weight of the brivaracetam sustained release preparation prepared by the formula 16 is preferably 500mg.
The weight of the brivaracetam sustained release preparation prepared by the formula 17 is preferably 1000mg.
The invention also aims to provide a preparation method of the brivaracetam sustained-release preparation, which comprises the following steps: (1) Pretreating each component in the brivaracetam sustained-release preparation; (2) Premixing components except the lubricant in the brivaracetam sustained release preparation; (3) Totally mixing the premixed material obtained in the step (2) with a lubricant; and (4) tabletting the materials which are mixed in the step (3).
The preparation method of the brivaracetam sustained-release preparation comprises the following steps: (1) Sieving each component of the brivaracetam sustained release preparation, wherein the mesh number of the sieve is 40 meshes;
(2) Premixing components except the lubricant in the brivaracetam sustained release agent for 15min;
(3) Totally mixing the premixed material obtained in the step (2) with a lubricant for 5min;
(4) And (4) tabletting the materials mixed in the step (3), wherein the hardness of the tablets is 18-25kg.
On the basis of the common knowledge in the field, the above preferred conditions can be combined randomly to obtain the preferred embodiments of the invention.
The reagents and starting materials used in the present invention are commercially available.
The positive progress effects of the invention are as follows: (1) The sustained-release preparation disclosed by the invention simultaneously comprises the ionic skeleton sustained-release material and the neutral skeleton sustained-release material, and the use of the ionic skeleton sustained-release material can keep the release of the preparation at a certain rule, reduce the food effect, ensure high safety and avoid the influence of the internal environment and external force of a receptor. (2) The combination of the two skeleton slow release materials makes the release curve easier to adjust, thereby achieving the once-a-day administration dosage. Compared with the commercial preparation, the invention can reduce the administration times and improve the compliance of patients. (3) The preparation method has the advantages of simple preparation process, short production period, low cost and easy production amplification.
Drawings
FIG. 1 shows the results of the pharmacokinetic experiments in beagle dogs.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the invention thereto. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
Examples 1 to 2
The tablet core is prepared by direct tabletting, and the weight of a single tablet is 700mg.
TABLE 1 core composition (%, w/w) of examples 1-2
| Name (R) | Example 1 | Example 2 |
| Brilliant's acid salt | 14.29 | 14.29 |
| Lactose | 49.71 | 49.71 |
| Sodium carboxymethylcellulose | 17.50 | 17.50 |
| Hydroxypropyl cellulose | 17.50 | / |
| Hydroxypropyl methylcellulose | / | 17.50 |
| Magnesium stearate | 1.00 | 1.00 |
The preparation process comprises the following steps:
(1) Pretreatment: respectively sieving the raw materials and the auxiliary materials with a 40-mesh sieve;
(2) Premixing: weighing other raw materials except magnesium stearate, and mixing for 15min;
(3) Total mixing: adding magnesium stearate, and mixing for 5min;
(4) Tabletting: tabletting the total mixed materials, and controlling the hardness to be 18-25kg.
Examples 3 to 5
The tablet core is prepared by direct tabletting, and the weight of a single tablet is 700mg. The preparation process is the same as in example 1-2.
TABLE 2 core composition (%, w/w) of examples 3-5
Examples 6 to 8
The tablet core is prepared by direct tabletting, and the weight of a single tablet is 700mg. The preparation process was the same as in example 1-2.
TABLE 3 core composition (%, w/w) of examples 6-8
Examples 9 to 14
The tablet core is prepared by direct tabletting, and the weight of a single tablet is 600mg. The preparation process is the same as in example 1-2.
TABLE 4 core composition (%, w/w) of examples 9-14
Examples 15 to 17
The tablet core of the present invention is prepared by direct compression as follows. The preparation process was the same as in example 1-2.
TABLE 5 core composition (%, w/w) of examples 15-17
Example 18: measurement of release rate of brivaracetam sustained release preparation under different pH conditions
According to 0931 dissolution and release determination method (second method, 50rpm, 900mL dissolution medium) in the four-part general rule of "Chinese pharmacopoeia" 2020 edition, the release characteristics of tablets are determined at 16h time intervals, and the release rates in a hydrochloric acid solution at pH1.2, an acetate buffer solution at pH4.5 and a phosphate buffer solution at pH6.8 are determined at 37 deg.C, respectively (in%,% means the mass of the released pharmaceutical active ingredient in the total mass of the pharmaceutical active ingredient in the preparation).
TABLE 6 Release (%) versus time (h) for examples 1-17
Comparative example 1
Tablet cores of the following composition were prepared by direct compression, with a tablet weight of 700mg. The preparation process was the same as in example 1-2.
TABLE 7 core composition (%, w/w) of comparative example 1
| Brilliant's acid salt | Lactose | Hydroxypropyl cellulose | Hydroxypropyl methylcellulose | Magnesium stearate |
| 14.29 | 49.71 | 17.50 | 17.50 | 1.00 |
TABLE 8 Release (%) of comparative example 1 as a function of time (h)
From the effects of examples 1 and 2 and comparative example 1, it can be seen that when the matrix sustained-release material of the tablet core contains sodium carboxymethylcellulose (ionic matrix sustained-release material, examples 1 and 2), at the same time point, examples 1 and 2 release the most rapidly in hydrochloric acid solution at ph1.2 and release the release curves in acetate buffer at ph4.5 and phosphate buffer at ph6.8, that is, release is faster in the gastrointestinal tract environment before eating and release is slower in the gastrointestinal tract environment after eating, which can reduce the food effect. When the skeleton sustained-release material of the tablet core does not contain sodium carboxymethylcellulose (ionic skeleton sustained-release material), the release of the comparative example 1 is fastest in a phosphate buffer solution with the pH value of 6.8, second in a hydrochloric acid solution with the pH value of 1.2 and slowest in an acetate buffer solution with the pH value of 4.5. This shows that the sustained release agent without the ionic matrix sustained release material is released quickly in the gastrointestinal tract environment after eating, is easily influenced by the in vivo environment, has strong food effect, and may cause the in vivo burst release to influence the safety.
According to the relation between the release and the time of the examples 3-5, when the ionic skeleton slow release material sodium carboxymethylcellulose in the tablet core is replaced by the ionic skeleton slow release material carbomer, the examples 3-5 release the sodium carboxymethylcellulose in hydrochloric acid solution with pH value of 1.2 most quickly, and release the sodium carboxymethylcellulose in acetate buffer solution with pH value of 4.5 and phosphate buffer solution with pH value of 6.8 slower and the release curves are similar. The release profile was in accordance with example 1-2.
With reference to examples 1-17, when one of the sustained-release matrix materials in the tablet core is an ionic matrix sustained-release material, the neutral matrix sustained-release materials are adjusted to be a hydrophilic gel matrix material, a waxy material and an insoluble matrix material, and the examples all maintain consistent release rules: at the same time point, examples 1-17 all released the fastest in the hydrochloric acid solution at ph1.2, released slower and at similar rates in acetate buffer at ph4.5 and phosphate buffer at ph6.8, and were able to reduce food effect. In addition, the brivaracetam sustained release agent of example 2, example 5, example 7, example 8, example 9, example 10, example 11, example 12 and example 17 has a lower release rate, a slow release rate and the slowest release rate at the 16 hour time point in example 2, example 5, example 7, example 8, example 9, example 10, example 11, example 12 and example 17.
Example 19 Biggee in vivo pharmacokinetic experiments
Healthy adult beagle dogs, 6 dogs, were randomly divided into 2 groups (fasting group, fed group), 3 dogs each, and the experiment was performed as in example 1, one at a time. Fasting for 12h before the experiment, and administering 150g of lipid (half fat lean minced pork) each to the fed group at the experiment, and then administering; the fasting group was given 100ml of water, followed by administration. Meals were scheduled simultaneously 8h after dosing. Each group of dogs take 3ml of blood through the great saphenous vein in 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 and 36 hours, heparin is used for anticoagulation, plasma samples are taken by low-temperature centrifugation, and the blood is frozen at low temperature for detection. Two groups of dogs after 2 weeks were crossed with the test, namely, the beagle dogs in the fasting group were taken as the fed group two weeks later, and the beagle dogs in the fed group were taken as the fasting group two weeks later, and the test procedure was as before.
According to the result of the in vivo pharmacokinetics experiment of beagle dogs, the Cmax of the fasting group is 1.12 times that of the fed group, and the AUC of the fasting group is 1.05 times that of the fed group, and the Cmax and the AUC are not significantly different. The results in fig. 1 show that the sustained-release brixitan tablet of the present invention shows less food effect and is highly safe in vivo. Examination of the binding release profile presumably leads to the following: the drug in the embodiment is released faster in hydrochloric acid solution with pH1.2, and released slower and similar release curves in acetate buffer with pH4.5 and phosphate buffer with pH6.8, namely, the drug is released faster in gastrointestinal tract environment before eating and released slower in gastrointestinal tract environment after eating, thereby reducing food effect; meanwhile, after eating, the skeleton tablet is released and accelerated under the external force action of food extrusion and gastrointestinal peristalsis to achieve a similar release rate before eating, so that the food effect is reduced, and the risk of sudden release in vivo after eating is reduced.
In conclusion, the invention provides a sustained-release brivaracetam preparation which simultaneously contains an ionic skeleton sustained-release material and a neutral skeleton sustained-release material, shows smaller food effect and can reduce the risk of in-vivo burst release after eating.
Claims (14)
1. A brivaracetam sustained-release preparation, which is characterized by comprising: the active drug component comprises brivaracetam, a brivaracetam pharmaceutically acceptable complex, salt, solvate and hydrate thereof or a plurality of brivaracetam pharmaceutically acceptable complexes, salt, solvate and hydrate thereof.
2. The brivaracetam sustained-release preparation according to claim 1, further comprising a filler and a lubricant.
3. The sustained-release brivaracetam preparation according to claim 1, which comprises an active pharmaceutical ingredient, an ionic matrix sustained-release material, a neutral matrix sustained-release material, a filler and a lubricant, wherein the active pharmaceutical ingredient is one or more of brivaracetam, a brivaracetam pharmaceutically acceptable complex, a salt thereof, a solvate thereof and a hydrate thereof.
4. The brivaracetam sustained-release preparation according to claim 2, wherein the active pharmaceutical ingredient is used in an amount of 10.00-33.33%, wherein the percentage is the weight of the active pharmaceutical ingredient relative to the total weight of the preparation composition;
and/or the dosage of the ionic skeleton slow-release material is 2.00-45.00 percent, and the percentage refers to the weight of the ionic skeleton slow-release material accounting for the total weight of the preparation composition;
and/or, the dosage of the neutral skeleton slow release material is 5.00-50.00%, and the percentage refers to the weight of the neutral skeleton slow release material accounting for the total weight of the preparation composition;
and/or the dosage of the filler is 2.33-65.33%, and the percentage refers to the weight of the filler accounting for the total weight of the preparation composition;
and/or the lubricant is used for supplementing the balance to 100.00 percent, wherein the percentage refers to the weight of the lubricant to the total weight of the preparation composition.
5. The brivaracetam sustained-release preparation according to claim 4, wherein the active pharmaceutical ingredient is used in an amount of 14.29%, 16.67% or 20.00%, wherein the percentage is the weight of the active pharmaceutical ingredient relative to the total weight of the preparation composition;
and/or the dosage of the ionic skeleton slow-release material is 5.00%, 10.00%, 12.50%, 15.00%, 17.50%, 20.00% or 30.00%, and the percentage refers to the weight of the ionic skeleton slow-release material in the total weight of the preparation composition;
and/or the dosage of the neutral skeleton slow release material is 15.00-45%, preferably 17.50%, 30.00%, 35.00% or 40.00%, and the percentage refers to the weight of the neutral skeleton slow release material accounting for the total weight of the preparation composition;
and/or, the filler is used in an amount of 10.67%, 16.83%, 29.00%, 36.33%, 37.33%, 45.33%, 49.71%, 54.71% or 64.00%, wherein the percentage refers to the weight of the filler relative to the total weight of the formulation composition;
and/or, the lubricant is used in an amount of 1.00-3.00%, preferably 1.50% or 2.00%, wherein the percentage refers to the weight of the lubricant to the total weight of the preparation composition.
6. The brivaracetam sustained release formulation of claim 3, consisting of: the dosage of the active pharmaceutical ingredient is 10.00-16.67%, and the percentage refers to the weight of the active pharmaceutical ingredient accounting for the total weight of the preparation composition;
the dosage of the ionic skeleton slow-release material is 10.00-45.00%, and the percentage refers to the weight of the ionic skeleton slow-release material accounting for the total weight of the preparation composition;
the dosage of the neutral skeleton slow release material is 15.00-45.00 percent, and the percentage refers to the weight of the neutral skeleton slow release material accounting for the total weight of the preparation composition;
the dosage of the filler is 2.33-64.00%, and the percentage refers to the weight of the filler accounting for the total weight of the preparation composition;
the dosage of the lubricant is 1.00-2.00%, and the percentage refers to the weight of the lubricant accounting for the total weight of the preparation composition.
7. The brivaracetam sustained release formulation of claim 3, consisting of: the dosage of the active pharmaceutical ingredient is 10.00-16.67%, and the percentage refers to the weight of the active pharmaceutical ingredient accounting for the total weight of the preparation composition;
the dosage of the ionic skeleton slow-release material is 10.00-45.00%, and the percentage refers to the weight of the ionic skeleton slow-release material accounting for the total weight of the preparation composition;
the dosage of the neutral skeleton slow release material is 15.00-35.00%, and the percentage refers to the weight of the neutral skeleton slow release material in the total weight of the preparation composition;
the dosage of the filler is 2.33-4.00%, and the percentage refers to the weight of the filler accounting for the total weight of the preparation composition;
the dosage of the lubricant is 1.00 percent, and the percentage refers to the weight of the lubricant to the total weight of the preparation composition.
8. The brivaracetam sustained-release preparation according to claim 2, wherein the active pharmaceutical ingredient is brivaracetam;
and/or the ionic type skeleton slow-release material is one or more of sodium carboxymethylcellulose, carbomer, alginate, arabic gum, xanthan gum, acrylic acid polymer and methacrylic acid copolymer, and preferably the sodium carboxymethylcellulose and/or the carbomer;
and/or the neutral skeleton slow-release material is one or more of a hydrophilic gel skeleton material, a waxy material and an insoluble skeleton material;
and/or the filler is one or more of lactose, microcrystalline cellulose, silicified microcrystalline cellulose, mannitol, pregelatinized starch, sucrose, calcium hydrogen phosphate, starch and dextrin, preferably lactose;
and/or the lubricant is one or more of magnesium stearate, talcum powder, colloidal silicon dioxide and calcium stearate, and the magnesium stearate is preferred.
9. The brisitan sustained release formulation according to claim 8, wherein the hydrophilic gel matrix material is one or more of hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose and polyoxyethylene, preferably one or more of hydroxypropyl cellulose, hydroxypropyl methylcellulose and hydroxyethyl cellulose;
and/or the waxy material is one or more of glyceryl behenate, stearic acid, stearyl alcohol, hydrogenated castor oil, carnauba wax and paraffin, preferably glyceryl behenate;
and/or the insoluble framework material is one or more of ethyl cellulose, polyacrylic resin, polyvinyl acetate povidone mixture, ethylene-vinyl acetate copolymer and cellulose acetate, preferably the ethyl cellulose and/or polyvinyl acetate povidone mixture.
10. The sustained-release brivaracetam preparation according to claim 1, wherein the dosage form of the brivaracetam preparation is a tablet, and the tablet weight of the tablet is 300mg to 1000mg, preferably 700mg, 600mg or 500mg.
11. The sustained release preparation of brivaracetam as claimed in claim 3, wherein the sustained release preparation of brivaracetam is formula 1, wherein the formula 1 is composed of 14.29% of brivaracetam, 49.71% of lactose, 17.50% of sodium carboxymethylcellulose, 17.50% of hydroxypropyl cellulose and 1.00% of magnesium stearate, and the percentages are ratios of the weight of each component relative to the total weight of the preparation composition;
or the sustained-release preparation of the brivaracetam is a formula 2, wherein the formula 2 consists of 14.29 percent of brivaracetam, 49.71 percent of lactose, 17.50 percent of sodium carboxymethylcellulose, 17.50 percent of hypromellose and 1.00 percent of magnesium stearate, and the percentages are the weight ratio of each component relative to the total weight of the preparation composition;
or, the sustained-release preparation of the brivaracetam is a formula 3, wherein the formula 3 consists of 14.29% of brivaracetam, 54.71% of lactose, 17.50% of hydroxypropyl cellulose, 12.50% of carbomer and 1.00% of magnesium stearate, and the percentages are the weight ratio of each component relative to the total weight of the preparation composition;
or, the sustained-release preparation of the brivaracetam is a formula 4, wherein the formula 4 consists of 14.29 percent of brivaracetam, 54.71 percent of lactose, 17.50 percent of hydroxyethyl cellulose, 12.50 percent of carbomer and 1.00 percent of magnesium stearate, and the percentages are the weight ratio of each component relative to the total weight of the preparation composition;
or the sustained-release preparation of the brivaracetam is a formula 5, wherein the formula 5 comprises 14.29% of brivaracetam, 54.71% of lactose, 17.50% of hypromellose, 12.50% of carbomer and 1.00% of magnesium stearate, and the percentages are the ratio of the weight of each component to the total weight of the preparation composition;
or, the brivaracetam sustained-release preparation is a formula 6, wherein the formula 6 consists of 14.29% of brivaracetam, 49.71% of lactose, 17.50% of glyceryl behenate, 17.50% of sodium carboxymethylcellulose and 1.00% of magnesium stearate, and the percentages are the weight ratio of each component relative to the total weight of the preparation composition;
or, the sustained-release preparation of the brivaracetam is a formula 7, wherein the formula 7 consists of 14.29 percent of brivaracetam, 49.71 percent of lactose, 17.50 percent of ethyl cellulose, 17.50 percent of sodium carboxymethyl cellulose and 1.00 percent of magnesium stearate, and the percentages are the weight ratio of each component relative to the total weight of the preparation composition;
or, the sustained-release preparation of the brivaracetam is a formula 8, the formula 8 consists of 14.29 percent of brivaracetam, 49.71 percent of lactose, 17.50 percent of polyvinyl acetate povidone mixture, 17.50 percent of sodium carboxymethyl cellulose and 1.00 percent of magnesium stearate, and the percentages are the weight ratio of each component relative to the total weight of the preparation composition;
or, the sustained-release preparation of the brivaracetam is a formula 9, wherein the formula 9 consists of 16.67% of brivaracetam, 37.33% of lactose, 15.00% of ethyl cellulose, 30.00% of sodium carboxymethyl cellulose and 1.00% of magnesium stearate, and the percentages are the weight ratio of each component relative to the total weight of the preparation composition;
or, the sustained-release brivaracetam preparation is a formula 10, wherein the formula 10 consists of 16.67% of brivaracetam, 16.83% of lactose, 45.00% of glyceryl behenate, 20.00% of sodium carboxymethylcellulose and 1.50% of magnesium stearate, and the percentages are the weight ratio of each component relative to the total weight of the preparation composition;
or, the sustained-release preparation of the brivaracetam is a formula 11, wherein the formula 11 consists of 16.67% of brivaracetam, 36.33% of lactose, 35.00% of ethyl cellulose, 10.00% of sodium carboxymethyl cellulose and 2.00% of magnesium stearate, and the percentages are the weight ratio of each component relative to the total weight of the preparation composition;
or, the sustained-release preparation of the brivaracetam is a formula 12, the formula 12 consists of 16.67% of brivaracetam, 2.33% of lactose, 35.00% of polyvinyl acetate povidone mixture, 45.00% of sodium carboxymethyl cellulose and 1.00% of magnesium stearate, and the percentages are the weight ratio of each component relative to the total weight of the preparation composition;
or, the sustained-release preparation of the brivaracetam is a formula 13, wherein the formula 13 consists of 16.67% of brivaracetam, 45.33% of lactose, 30.00% of hypromellose, 5.00% of sodium carboxymethylcellulose and 3.00% of magnesium stearate, and the percentages are the weight ratio of each component to the total weight of the preparation composition;
or, the sustained-release preparation of the brivaracetam is a formula 14, the formula 14 consists of 16.67% of brivaracetam, 65.33% of lactose, 15.00% of polyvinyl acetate povidone mixture, 2.00% of sodium carboxymethyl cellulose and 1.00% of magnesium stearate, and the percentages are the weight ratio of each component relative to the total weight of the preparation composition;
or, the sustained-release preparation of the brivaracetam is a formula 15, wherein the formula 15 consists of 33.33 percent of brivaracetam, 10.67 percent of lactose, 40.00 percent of polyvinyl acetate povidone mixture, 15.00 percent of sodium carboxymethyl cellulose and 1.00 percent of magnesium stearate, and the percentages are the weight ratio of each component relative to the total weight of the preparation composition;
or, the sustained-release preparation of the brivaracetam is a formula 16, wherein the formula 16 consists of 20.00 percent of brivaracetam, 29.00 percent of lactose, 35.00 percent of ethyl cellulose, 15.00 percent of sodium carboxymethyl cellulose and 1.00 percent of magnesium stearate, and the percentages are the weight of each component relative to the total weight of the preparation composition;
or, the sustained-release preparation of the brivaracetam is a formula 17, wherein the formula 17 consists of 10.00% of brivaracetam, 64.00% of lactose, 15.00% of hydroxypropyl cellulose, 10.00% of sodium carboxymethyl cellulose and 1.00% of magnesium stearate, and the percentages are the weight ratio of each component relative to the total weight of the preparation composition.
12. The brivaracetam sustained-release preparation according to claim 11, wherein the brivaracetam sustained-release preparation prepared from formula 1 to formula 8 has a tablet weight of 700mg;
the weight of the brivaracetam sustained release tablet prepared by the formula 9-the formula 14 is 600mg;
the weight of the brivaracetam sustained release preparation prepared by the formula 15 is 300mg;
the weight of the brivaracetam sustained release tablet prepared by the formula 16 is 500mg;
the weight of the brivaracetam sustained release tablet prepared by the formula 17 is 1000mg.
13. A process for preparing a brisitant sustained release formulation as claimed in any one of claims 1 to 12, which comprises the steps of: (1) Pretreating each component in the brivaracetam sustained release preparation;
(2) Premixing components except a lubricant in the brivaracetam sustained-release preparation;
(3) Totally mixing the premixed material obtained in the step (2) with a lubricant;
(4) And (4) tabletting the materials mixed in the step (3).
14. The method for preparing a brivaracetam sustained release preparation according to claim 13, comprising the steps of: (1) Sieving each component in the brivaracetam sustained release preparation, wherein the mesh number of the sieve is 40 meshes;
(2) Premixing components except the lubricant in the brivaracetam sustained release agent for 15min;
(3) Totally mixing the premixed material obtained in the step (2) with a lubricant for 5min;
(4) And (4) tabletting the materials mixed in the step (3), wherein the hardness of the tablets is 18-25kg.
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| CN1555801A (en) * | 2003-12-31 | 2004-12-22 | 广州知本源科技有限公司 | Naipaidil slow release preparation |
| CN101181259A (en) * | 2007-11-19 | 2008-05-21 | 青岛黄海制药有限责任公司 | Sustained-release agent of nitric acid dinitrate and preparation method thereof |
| CN101283993A (en) * | 2008-06-10 | 2008-10-15 | 北京赛诺源医药科技有限公司 | Use of the diabecron sustained-release tablet in treating the type 2 diabetes mellitus |
| CN103432093A (en) * | 2013-08-31 | 2013-12-11 | 西南大学 | Pridinol methanesulfonate matrix sustained-release tablet and preparation method thereof |
| CN105193803A (en) * | 2014-06-30 | 2015-12-30 | 北京斯利安制药有限公司 | Ilepcimide sustained release preparation and preparation method thereof |
| CN111407738A (en) * | 2020-04-03 | 2020-07-14 | 江苏艾立康药业股份有限公司 | Brivaracetam controlled-release preparation and preparation method thereof |
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2021
- 2021-07-08 CN CN202110773353.5A patent/CN115590830A/en not_active Withdrawn
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1555801A (en) * | 2003-12-31 | 2004-12-22 | 广州知本源科技有限公司 | Naipaidil slow release preparation |
| CN101181259A (en) * | 2007-11-19 | 2008-05-21 | 青岛黄海制药有限责任公司 | Sustained-release agent of nitric acid dinitrate and preparation method thereof |
| CN101283993A (en) * | 2008-06-10 | 2008-10-15 | 北京赛诺源医药科技有限公司 | Use of the diabecron sustained-release tablet in treating the type 2 diabetes mellitus |
| CN103432093A (en) * | 2013-08-31 | 2013-12-11 | 西南大学 | Pridinol methanesulfonate matrix sustained-release tablet and preparation method thereof |
| CN105193803A (en) * | 2014-06-30 | 2015-12-30 | 北京斯利安制药有限公司 | Ilepcimide sustained release preparation and preparation method thereof |
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