CN114469880B

CN114469880B - Pregabalin composition suitable for powder tabletting and application thereof

Info

Publication number: CN114469880B
Application number: CN202210155830.6A
Authority: CN
Inventors: 梁文伟; 刘锋; 谭晓峰; 李俊遇
Original assignee: AC Pharmaceuticals Co Ltd
Current assignee: AC Pharmaceuticals Co Ltd
Priority date: 2022-02-21
Filing date: 2022-02-21
Publication date: 2024-02-02
Anticipated expiration: 2042-02-21
Also published as: WO2023155682A1; CN114469880A

Abstract

The invention discloses a pregabalin composition suitable for powder tabletting, which comprises the active component pregabalin with square crystal habit, wherein the particle size range is D90:350-600 mu m, and the dosage of the pregabalin composition is 20-50% of the total weight of a prescription. The pregabalin composition also comprises a filler, a disintegrating agent, a flavoring agent, essence and a lubricant. The invention provides another idea, and by preparing the pregabalin raw material medicine with a certain grain size range and a specific crystal habit, compared with the common pregabalin raw material medicine, the compressibility of the prepared total mixed material is obviously improved, and the production cost is reduced.

Description

Pregabalin composition suitable for powder tabletting and application thereof

Technical Field

The invention belongs to the field of medicines, and particularly relates to a pregabalin composition suitable for powder tabletting.

Background

Internationally, the pregabalin quick-release oral solid preparation on the market is a tablet, a capsule and an orally disintegrating tablet. Compared with common tablets and capsules, the orally disintegrating tablet can rapidly disintegrate in the oral cavity in the absence of water or in the presence of only a small amount of water, and is particularly suitable for old people, children and dysphagia patients.

Pregabalin or (S) - (+) -3-aminomethyl-5-methyl-hexanoic acid can bind to the alpha-2-delta (α2δ) subunit of calcium channels and is involved in endogenous inhibitory neurotransmitter gamma-aminobutyric acid (GABA) associated with modulation of brain neuronal activity. Pregabalin has anti-seizure activity, as described in U.S. Pat. No. 5,563,175, and is useful in the treatment of: epilepsy, pain, physiological conditions associated with psychomotor stimulants, inflammation, gastrointestinal damage, alcoholism, insomnia, fibromyalgia, and various psychotic disorders including anxiety, depression, mania, and bipolar disorder. Pregabalin has been approved in the united states for the treatment of diabetic peripheral neuropathy, post herpetic neuralgia, and as an adjunct treatment for adult partial seizures. Pregabalin may be used as an Immediate Release (IR) formulation in a capsule and administered to a patient 2 or 3 times daily (BID or TID). Most patients are more prone to take the drug once a day than 2 or more times a day, especially for elderly patients and patients taking multiple drugs, and modes of administration of 1 time a day can generally improve patient compliance. Once daily administration may also reduce or avoid potential side effects by reducing the maximum concentration of drug in the blood (CMAX) and may also increase drug efficacy by increasing the minimum concentration in the blood (CMIN).

Oral pharmaceutical compositions containing pregabalin present a great challenge to formulation. The pregabalin drug molecule is an antagonist of gamma-amino acid (GABA) protein receptors. Mixing with various adjuvants, wherein filler adjuvants such as lactose can accelerate intramolecular cyclization of pregabalin to produce lactam impurity. Most of pregabalin raw materials are crystalline crystal particles, so that the compressibility is poor, and the conventional powder direct compression or dry granulation requirements cannot be met. The powder direct tabletting process is suitable for medicines which are easy to change color, decompose and the like when wet and heat, has the most remarkable advantages of reducing the equipment and operation cost, and the material particles for directly tabletting the powder have good fluidity, compressibility and certain fineness or crystallization form, otherwise, the phenomena of plug punching, unqualified product properties and the like are easy to occur in the production process. Therefore, the improvement of the compressibility of the materials is a difficulty in preparing the pregabalin orally disintegrating tablet preparation.

Pregabalin is a polymorphic drug, including anhydrous, semi-anhydrous, forms I-IV, and alpha form. The specific crystalline form combination of a polymorphic drug has a significant impact on the physical properties of the product, such as storage, stability, compressibility, bulk density (which has a significant impact in formulation and product production) and dissolution (which has a significant impact in determining bioavailability). On the other hand, a characteristic that crystals spontaneously grow under certain external conditions to tend to form a certain morphology is called crystal habit. Crystal habit is an abbreviation for crystal habit, also known as crystal habit, and crystal habit. The classification of the crystal habit is usually descriptive and not very strict, and it is difficult to find a definite number of categories and classification criteria. The common crystal habit classification can be classified into lamellar, dendritic, knife-edge, needle-like, lenticular and lamellar according to the crystal appearance; according to the crystal face and the crystal face clamp angle, the method comprises the following steps: prisms, pyramids, plates; according to polyhedrons, the method is divided into: cubes, octahedrons, dodecahedrons; according to the aggregation state of single crystals, it is classified into: fibrous, grape, radial, block; multiple crystalline forms of the same substance may also exist. The physical properties of the drug form and crystal habit are very important in pharmaceutical processing, and may affect the compressibility and flowability of the intermediate product.

CN00812588 provides a method for preparing immediate release drug taste-masking granules by granulating a mixed powder of active substance, granule disintegrant, osmotic agent and sweetener using a binder, and then coating taste-masking using a coating agent. However, the method has more process steps, the dissolution rate of the coated product is about 10 percent slower than that of a reference preparation (Lyrica) for 5min, the quick release cannot be realized, the bioavailability is low, the coated tablet can only be swallowed, cannot be chewed, and the actual administration convenience is low.

CN103271888 mentions that the crude drug of pregabalin has poor compressibility, and provides a prescription of pregabalin drug (10% -50%), disintegrant-crosslinked povidone (5% -30%), microcrystalline cellulose (20% -80%), and the balance of corrigent, glidant and lubricant; the preparation process comprises the following steps: mixing pregabalin, correctant, microcrystalline cellulose and disintegrating agent in wet granulator, adding appropriate amount of water, granulating, drying, sieving, mixing with the rest adjuvants, and pressing into tablet with required hardness. The pregabalin orally disintegrating tablet developed by the invention overcomes the problem of poor compressibility of pregabalin. According to the invention, multiple experiments show that the compressibility of the material can be improved through a granulating process, but the product pressed by the granulated material has obvious taste problem, and the taste is gritty and the disintegrating speed is slower; the finished product prepared by the powder direct-compression process is instantly melted in mouth, and has soft and glutinous mouthfeel. Therefore, in order to preserve the soft waxy taste of the orally disintegrating tablets of pregabalin, the product taste should not be abandoned in order to use the granulation process to improve the compressibility of the material. Meanwhile, the process steps are complex, the wet granulation process is high in energy consumption and long in time consumption, and the wet and hot conditions in the processing process can cause unnecessary stability risks.

CN111096953 provides a pregabalin orally disintegrating tablet directly tabletable with silicified microcrystalline cellulose powder and a method for preparing the same. The pregabalin is premixed with silicified microcrystalline cellulose, then mixed with other auxiliary materials, and then subjected to powder direct compression. The prescription proportion of the medicine is pregabalin medicine (10% -30%), disintegrating agent crosslinked povidone (5% -20%), filler silicified microcrystalline cellulose, spray-dried mannitol 200SD (10% -80%), lubricant (0.5% -2%), flavoring agent (1% -3%). The method can improve the compressibility and fluidity of materials to ensure that the prepared orally disintegrating tablet has excellent stability. However, silicified microcrystalline cellulose is an expensive auxiliary material, the price of which is 3 to 4 times that of general microcrystalline cellulose, and the prescription dosage proportion of microcrystalline cellulose is 20 to 40 percent, and the increase of the cost is unfavorable for the market sales of products.

In general, improving the compressibility of granules during the preparation of orally disintegrating tablets of pregabalin may be considered by adding excipients with better compressibility or reducing the proportion of pregabalin in the prescription, but this causes problems of increasing the tablet weight and increasing the size, and also reduces the number of tablets produced in a single batch. The way of adding the adhesive can influence the disintegration behavior of the product and prolong the disintegration time of the product. The compressibility of the granules can be effectively improved by adopting a wet granulation mode, but the process can increase the processing cost, the time and other cost in preparation, and meanwhile, the risk of increasing impurities of the product can be increased by contacting with damp-heat factors. At present, most methods for improving the compressibility of granules in the preparation process of pregabalin orally disintegrating tablets are by adding auxiliary materials with better compressibility or performing wet granulation, and the methods can increase the cost of the products and influence the disintegration time limit conditions of the products

Disclosure of Invention

The invention aims to: aiming at the defects of the prior art, the invention provides the pregabalin composition suitable for powder tabletting, and the pregabalin orally disintegrating tablet with excellent quality can be prepared by selecting bulk drugs with specific crystal habit and particle size range, further compounding with a filler, a lubricant and a disintegrating agent, and obviously improving the material compressibility and through a simple mixed tabletting process.

In order to solve the technical problems, the invention discloses a pregabalin composition suitable for powder tabletting, wherein the active component pregabalin is pregabalin with square crystal habit, the grain diameter range is D90:350-600 mu m, and the dosage is 20-50% of the total weight of the prescription.

The pregabalin composition also comprises a filler, a disintegrating agent, a flavoring agent, essence and a lubricant.

Specifically, the dosage of the filler is 0.0% -80.0%, the flavoring agent is 0.1% -15.0%, the disintegrating agent is 1.0% -20.0%, the lubricant is 0.5% -3.0%, preferably, the dosage of the filler is 30.0% -70.0%, the flavoring agent is 1.0% -5.0%, the disintegrating agent is 1.0% -10.0%, the lubricant is 0.5% -3.0%, and the glidant is 0.1% -1.0%, wherein the percentages account for the total mass of the prescription.

Wherein the filler is any one or two of cellulose derivative and starch derivative. Further, the filler is, for example, cyclodextrin, dextrin, microcrystalline cellulose, pregelatinized starch, sodium carboxymethyl starch, mannitol, sorbitol, xylitol, glucose, methylcellulose, hydroxypropyl starch, or the like; preferably, the filler is at least one of microcrystalline cellulose, dibasic calcium phosphate dihydrate, mannitol, or lactose.

The disintegrating agent is at least one of crosslinked sodium carboxymethyl cellulose, crosslinked povidone, low-substituted hydroxypropyl cellulose or sodium carboxymethyl starch; the glidant is one or more of micropowder silica gel, talcum powder and magnesium stearate.

The lubricant is at least one of sodium stearyl fumarate, magnesium stearate, micro silica gel and talcum powder.

The flavoring agent is one or more of cyclohexyl sulfamate (sodium cyclamate), acesulfame potassium (acesulfame potassium, A-K sugar), aspartyl phenylalanine methyl ester (aspartame, sweetener), aspartame, neotame, sucralose, sucrose, sorbitol, mannitol and glucose; the essence is natural essence or artificially synthesized essence, preferably at least one of milk essence, grape essence, strawberry essence, vanillin, apple essence, orange essence, banana essence, orange oil and other natural essence or artificially synthesized essence.

The composition also comprises a glidant, wherein the dosage of the glidant accounts for 0.1-1.0% of the total mass of the prescription, and the glidant is any one or more of superfine silica powder, talcum powder and magnesium stearate.

The invention further provides application of the pregabalin composition in preparation of pregabalin tablets.

Furthermore, the invention provides a preparation method of the pregabalin tablet, which comprises the following steps:

(1) Granulating the raw materials by a gate type granulator, granulating the raw materials by the gate type granulator, and enabling the pregabalin to be pregabalin with square crystal habit after granulating, wherein the grain size range is D90:350-600 mu m;

(2) Mixing the raw materials except the lubricant, sieving, adding the lubricant, and mixing to obtain mixed particles;

(3) Pressing the mixed particles by a tablet press to obtain the tablet with the hardness of 4-6 kg.

Preferably, the sieve pore diameter of the granulator is 0.8mm, and the granulating rotating speed is 300-700rpm. The tablet prepared by the invention can be used for quick-release preparation for treating epilepsy and neuropathic pain.

The beneficial effects are that: compared with the prior art, the invention has the following advantages:

(1) The invention is obtained by a great deal of experiments and researches of the inventor: the pregabalin orally disintegrating tablet with excellent quality can be prepared by compounding the pregabalin bulk drug with the grain diameter range D90 of 350-600 mu m and square crystal habit, the filler, the lubricant and the disintegrating agent, and by a simple mixing tabletting process. The quick-release preparation can realize the quick release of the active ingredient pregabalin, so that the effective blood concentration can be reached quickly after oral administration; compared with the traditional capsule preparation, the quick-release preparation prepared by the invention has the effects of quick response, quick absorption and stability, has cool and slightly sweet taste, is instant in mouth feel, has soft and glutinous taste, does not have intolerable bitter taste, and can improve the compliance of patients.

(2) According to the preparation method, the pregabalin raw material medicine is processed by a gate type granulator to obtain the pregabalin raw material medicine with specific crystal habit and a certain particle size range, and then the pregabalin raw material medicine is mixed with various conventional auxiliary materials to prepare material particles with excellent compressibility by a relatively simple process, so that the pregabalin orally disintegrating tablet is prepared. The process has the advantages of simple operation, mature control standard, low cost, high industrialization degree and the like;

(3) According to the invention, stability research experiments on the reference preparation show that the low melting point of the lipid auxiliary material can influence the change of quality indexes of the product in the stability investigation process, such as appearance, related substances, dissolution, hardness and the like, and the use of the auxiliary material with higher price can increase the cost of the product. The invention simplifies the types of auxiliary materials, controls the grain diameter and crystal habit of the pregabalin bulk drug, and achieves the purposes of reducing the product cost and preparing stable pregabalin quick-release preparation.

Drawings

The foregoing and/or other advantages of the invention will become more apparent from the following detailed description of the invention when taken in conjunction with the accompanying drawings and detailed description.

FIG. 1 is a microscopic image of the drug substance used in product 1;

FIG. 2 is a microscopic photograph of the drug substance used in product 2;

FIG. 3 is a graph showing the particle size distribution of the crude drug used in product 1;

FIG. 4 is a graph showing the particle size distribution of the crude drug used in product 2;

FIG. 5 is a microscopic photograph of the crude drug used in product 3;

FIG. 6 is a microscopic photograph of the crude drug used in product 4;

FIG. 7 is a microscopic photograph of the drug substance used in product 5;

FIG. 8 is a microscopic photograph of the drug substance used in product 6;

fig. 9 is a microscopic image of the drug substance used in product 7.

Fig. 10 is a graph of the dissolution profile of product 1 and product 2 and the reference formulation.

Detailed Description

For a better understanding of the present invention, its advantages and benefits will be obtained from the following examples and experimental data of the present invention.

In the following examples, the product detection method is as follows:

the method for measuring and sampling the particle size of the bulk drug comprises the following steps:

in a material bag filled with the pregabalin bulk drug after granule finishing, 5g of each of the upper, middle and lower 6 different positions are sampled respectively, a sample is synthesized after sampling, 30g of the total sample is sampled, and the granularity distribution is detected by inspection.

The method for measuring the particle size of the bulk drug comprises the following steps:

the method for measuring the particle size of the bulk drug comprises the following steps: weighing about 0.3g of span-85 dispersant in a 250ml beaker, adding 120ml of accurately measured n-heptane to obtain span-85 n-heptane solution with a certain proportion, placing the span-85 n-heptane solution in a micro-disperser, stirring the solution until the background is stable, measuring the background signal, adding 0.1g of pregabalin sample, stirring the solution for 60s to obtain a sample to be detected with a certain concentration, placing the sample in a micro-wet sample injection window of a laser particle analyzer, running corresponding measurement method files according to related parameter items, and taking the arithmetic average value of 3 measurement results to obtain the particle size data of the bulk drug.

And (3) analyzing particle size data of the raw material medicines:

the particle size distribution means that the percentage of the particles with different particle diameters in the powder sample to the total volume (or number, etc.) of the particles is measured by a specific instrument and method. D10: the particle size distribution number reaches 10% by integrating one sample (self-adding the percentage of all the particle sizes before or after). Its physical meaning is that its particles with a particle size smaller (or larger) than 10%. D90: the particle size corresponding to the number of cumulative particle size distributions of one sample reaches 90%. Its physical meaning is that its particles with a particle size smaller (or larger) than 90%. D50: the particle size corresponding to a cumulative particle size distribution percentage of one sample reaching 50%. The physical meaning is that the particle size is greater than 50% of its particles, and less than 50% of its particles, also called median or median particle size, D50. It does not represent the average particle size of the powder, but represents the average particle size of the powder with other parameters such as D (4, 3), D (3, 2), etc. Both D (4, 3) and D (3, 2) represent the average particle size on a volume basis. Wherein D (4, 3) is collectively referred to as "mass moment volume average particle diameter" simply referred to as volume average diameter. The calculation method is that the particle size values at the two ends of each particle size interval are averaged, multiplied by the particle size distribution percentage corresponding to the interval, and the products are accumulated, namely D (4, 3) =f1.D1+f2.D2+f3.D3+ …. D (3, 2) is called "volume area average particle diameter" for short, area average diameter. The calculation method is to divide the percentage of each particle size interval by the average value of the corresponding particle size interval, and then accumulate the divided percentages, namely D (3, 2) =1/f (f1/D1+f2/D2+f3/D3+ …). Wherein: di represents the average particle diameter of the ith particle diameter section, and fi represents the ith particle diameter. The relationship between D (3, 2) and D (4, 3) can be understood as follows: for laser particle sizers, the more nearly spherical particles, the more accurate the measurement result. Then, when the values of D (3, 2) and D (4, 3) are closer, it is explained that the more regular the shape of the sample particles, the more concentrated the particle size distribution. The larger the difference, the more irregular the shape of the sample particles, the wider the particle size distribution.

The observation method of the crude drug crystal habit microscope comprises the following steps:

the crystal habit appearance of the crude drug is observed and measured by a microscope. 0.01g of pregabalin raw material medicine is taken on a glass slide, and 1 drop of liquid paraffin is dripped for dispersion. The microscope eyepiece parameter is 10 times, the objective lens parameter is 5 times, and the photo of uniform particle dispersion and sufficient illumination is observed and shot.

Flowability, tablet friability, method for determining highest tablet hardness:

100g of the total mixture was taken and the flowability of the material was determined using an FT-104B angle of repose meter. About 6.5g of the finished product was taken and subjected to tablet friability measurement using a CJY-300D type tablet friability measuring instrument. The hardness of the finished tablets was measured using a YPD-200C tablet hardness tester.

Example 1

Product 1 prescription form:

product 2 prescription form:

the preparation process flow of the product 1 comprises the following steps:

(1) carrying out gate type granule finishing machine granule finishing on pregabalin (D90 is 900 mu m, crystal habit is long needle-shaped and square), carrying out 0.8mm granule finishing screen, finishing speed is 700rpm, and after granule finishing, the pregabalin D90 is 500 mu m, and crystal habit is square;

(2) according to the dosage in the prescription table of the product 1, microcrystalline cellulose, pregabalin, mannitol, sucralose, saccharin sodium, crosslinked povidone SH-SL10 and peppermint essence are mixed by using a square cone mixing barrel at the mixing rotating speed of 10rpm for 20min;

(3) sieving the mixed particles obtained in the last step with a 20-mesh vibrating screen, adding magnesium stearate into the sieved particles, and mixing by using a square cone mixing barrel at a mixing rotating speed of 10rpm for 20min;

(4) the mixed granules obtained in the previous step are used for direct powder compression.

The preparation process flow of the product 2 comprises the following steps:

(1) according to the dosage in the prescription table of the product 2, pregabalin (D90 is 900 mu m, crystal habit is long needle-shaped and square), microcrystalline cellulose, mannitol, sucralose, saccharin sodium, crosslinked povidone SH-SL10 and peppermint essence are mixed by using a square cone mixing barrel, the mixing rotating speed is 10rpm, and the mixing time is 20min;

(2) sieving the mixed particles obtained in the last step with a 20-mesh vibrating screen, adding magnesium stearate into the sieved particles, and mixing by using a square cone mixing barrel at a mixing rotating speed of 10rpm for 20min;

(3) the mixed granules obtained in the previous step are used for direct powder compression.

The microscopic pictures of the raw materials used in the product 1 and the product 2 are shown in fig. 1 and fig. 2, and the particle size distribution of the raw materials used in the product 1 and the product 2 are shown in fig. 3 and fig. 4.

Bulk drug and tablet Properties

Experimental results and conclusions

The D90 of the bulk drug of the product 1 after being granulated by a gate granulator is 500 mu m, and the difference value between D (4, 3) and D (3, 2) is 74 mu m. The D90 of the crude drug of the product 2 is 900 mu m, and the difference value between D (4, 3) and D (3, 2) is 575 mu m. Compared with the product 2, the difference between the raw medicines D (3, 2) and D (4, 3) of the product 1 is small, which indicates that the raw medicine particles of the product 1 are more regular in shape and concentrated in particle size distribution, and then the crystal habit is square according to the microscopic photograph. The difference between the raw materials D (3, 2) and D (4, 3) of the product 2 is large, which indicates that the raw material particles of the product 2 are irregular in shape and wide in particle size distribution, and then according to a microscopic photograph, the crystal habit of the product 2 is heterogeneous mixed crystals of square crystals and long needle-shaped crystals.

The tablet result shows that the crystal habit is mainly cubic, the product 1 with the D90 of 500 mu m is better in material fluidity, lower in friability and higher in highest pressable hardness than the product 2 with the bulk drug crystal habit being mainly long needle-shaped crystals and mixed crystals of the cubic crystals. Therefore, the pregabalin bulk drug with crystal habit mainly being square crystals can effectively improve the fluidity and the compressibility of materials, and the pregabalin orally disintegrating tablet with excellent properties is prepared.

Fig. 10 is a graph of dissolution of product 1 and product 2 and a reference formulation. The detection is carried out by adopting a 0.06M HCL-paddle method, and the specific detection steps are as follows:

dissolution medium: 0.06M hydrochloric acid solution, configuration steps: weighing 5.4ml of hydrochloric acid, diluting to 1000ml with water, and shaking to obtain the final product.

Control solution: the pregabalin control was taken at about 16mg, precisely weighed, placed in a 100mL volumetric flask, dissolved with dissolution medium and diluted quantitatively to a scale, and shaken well (at a concentration of about 160 μg/mL). Two portions were prepared in parallel.

Mobile phase preparation:

(1) 0.04M diammonium phosphate (pH 6.5)

Precisely weighing 5.28g of diammonium hydrogen phosphate and ultrapure water, fixing the volume to 1000ml, regulating the pH value to 6.5+/-0.05 by using phosphoric acid, and carrying out suction filtration.

(2) Mobile phase: 0.04M diammonium phosphate (pH 6.5): acetonitrile=90:10

Dissolution conditions:

dissolution medium: 0.06M hydrochloric acid

Dissolution device: paddle method

Rotational speed: 50rpm

Dissolution medium temperature: 37+ -0.5 DEG C

Sampling volume, fluid infusion volume: 3.5ml of sample was taken, and 2ml of waste liquid was discarded without replenishing.

Volume of dissolution medium: 900ml.

Sample feeding mode: and (5) randomly sampling.

Sample solution treatment: the mixture was filtered using a 0.45 μm aqueous filter head (Zun, polyethersulfone, 25 mm), and 2ml of the primary filtrate was discarded, and the subsequent filtrate was taken as a sample solution.

Sampling time points: 5. 10, 15 (min).

High performance liquid chromatograph detection conditions:

chromatographic column: GL Sciences Inertsil ODS-3V.

The comparative preparation was a pregabalin orally disintegrating tablet, which was first marketed in Japan in 2017, 02 and 17, trade name LYRICA (Le Ruika), japanese trade name of the green OD spindle, pfizer Japan inc (feizer Japan), and the reference preparation was labeled EA6596 in this application. From the results, the dissolution curve of the product is similar to that of the reference preparation, and the in vitro results show that the product has the same effect as the reference preparation and quick absorption.

Example 2

Product 3 prescription form:

the preparation process flow of the product 3 comprises the following steps:

(1) carrying out gate type granule finishing machine granule finishing on pregabalin (D90 is 900 mu m, crystal habit is long needle-shaped and square), carrying out a 0.8mm granule finishing screen, reducing the granule finishing speed from 700rpm to 300rpm of the minimum rotating speed of equipment, and carrying out granule finishing on pregabalin D90 after granule finishing to 550 mu m, wherein the crystal habit is square;

(2) according to the dosage in the prescription table of the product 3, microcrystalline cellulose, pregabalin, mannitol, sucralose, saccharin sodium, crosslinked povidone SH-SL10 and peppermint essence are mixed by using a square cone mixing barrel, the mixing rotating speed is 10rpm, and the mixing time is 20min;

The microscopic picture of the crude drug used in the product 3 is shown in fig. 5.

Bulk drug and tablet Properties

Experimental results and conclusions

The rotation speed of the gate type granule finishing machine is reduced from 700rpm to 300rpm, and compared with the raw material medicine obtained by the rotation speed of 700rpm, the difference value between D90, D (4, 3) and D (3, 2) of the raw material medicine obtained by the rotation speed of 300rpm is not obviously changed. The tablet results show that compared with the product 1 of the bulk drug obtained at the rotational speed of 700rpm, the product 3 of the bulk drug obtained at the rotational speed of 300rpm has no obvious differences in material fluidity, friability of the tablet and highest pressable hardness. Therefore, 700rpm with higher production efficiency is used as the finishing rotation speed parameter of the gate type finishing machine after the process production, and the operation is simple and easy to control.

Example 3

Product 4 prescription form:

the preparation process flow of the product 4 comprises the following steps:

(1) the pregabalin (D90 is 900 μm, crystal habit is long needle-shaped and square) is subjected to the granulation of a gate type granulator, a 0.8mm granulating screen is changed into a 0.9mm screen, the granulating speed is 700rpm, and after the granulation, the pregabalin D90 is 700 μm, and the crystal habit is long needle-shaped and square.

(2) Mixing microcrystalline cellulose, pregabalin, mannitol, sucralose, saccharin sodium, crosslinked povidone SH-SL10 and peppermint essence according to the dosage in the prescription table of the product 4 by using a square cone mixing barrel at a mixing rotating speed of 10rpm for 20min;

A microscopic photograph of the drug substance used in product 4 is shown in fig. 6.

Bulk drug and tablet Properties

Experimental results and conclusions

The 0.8mm sieve of the gate type granulator is replaced by a 0.9mm sieve, and compared with the bulk drug obtained by the 0.8mm sieve, the difference value of D90, D (4, 3) and D (3, 2) of the bulk drug obtained by the 0.9mm sieve is obviously increased. By combining with the microscopic pictures of the raw materials, the pregabalin raw materials obtained by the 0.9mm screen mesh grain sizing are mixed crystals of long needle-shaped crystals and square crystals, and are not round as the raw materials obtained by the 0.8mm screen mesh grain sizing, and the whole grain size is bigger, and the D90 is 700 mu m. The tablet results show that compared with the product 1 of the bulk drug obtained by the 0.8mm screen, the product 4 of the bulk drug obtained by the 0.9mm screen has slower material fluidity, higher friability of the tablet, lower highest compressive hardness and slower disintegration time. Therefore, a screen with the thickness of 0.8mm is used as the screen parameter of the gate type granulator after the process production, the operation is simple and easy to control, and the product quality can be ensured.

Example 4

Product 5 prescription form:

the preparation process flow of the product 5 comprises the following steps:

(1) carrying out gate type granule finishing machine granule finishing on pregabalin (D90 is 900 mu m, crystal habit is long needle-shaped and square), changing a 0.8mm granule finishing screen into a 0.7mm screen, finishing the granule at 700rpm, and finishing the granule to obtain pregabalin D90 which is 350 mu m and crystal habit is square;

(2) according to the dosage in the prescription table of the product 5, microcrystalline cellulose, pregabalin, mannitol, sucralose, saccharin sodium, crosslinked povidone SH-SL10 and peppermint essence are mixed by using a square cone mixing barrel, the mixing rotating speed is 10rpm, and the mixing time is 20min;

A microscopic photograph of the drug substance used in product 5 is shown in fig. 7.

Bulk drug and tablet Properties

Experimental results and conclusions

The 0.8mm sieve of the gate type granulator is replaced by a 0.7mm sieve, and compared with the bulk drug obtained by the 0.8mm sieve, the difference value between D (4, 3) and D (3, 2) of the bulk drug obtained by the 0.7mm sieve is not obviously changed, but D90 is obviously reduced, and the whole particle size is obviously reduced. The microscopic pictures of the crude drugs are combined, so that the pregabalin crude drugs obtained by finishing the grains with a 0.7mm screen are square crystals and are round, but the whole grain size is smaller, and the D90 is 350 mu m. The tablet result shows that compared with the product 1 of the bulk drug obtained by the 0.8mm screen, the product 5 of the bulk drug obtained by the 0.7mm screen has no obvious change in material fluidity, slightly increased friability of the pressed tablet, slightly reduced highest compressible hardness, obviously slower disintegration time, presumably more fine powder of the bulk drug, easily adheres to the screen of a disintegration apparatus during disintegration, cannot pass smoothly, and leads to longer disintegration time. Therefore, a screen with the thickness of 0.8mm is used as the screen parameter of the gate type granulator after the process production, the operation is simple and easy to control, and the product quality can be ensured.

Example 5

Product 6 prescription form:

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the preparation process flow of the product 6 comprises the following steps:

(1) pulverizing pregabalin (D90 is 900 μm, crystal habit is long needle shape and square shape) with traditional Chinese medicine pulverizer for 4s to obtain pulverized pregabalin D90 is 200 μm, crystal habit is square shape;

(2) mixing microcrystalline cellulose, crushed pregabalin, mannitol, sucralose, saccharin sodium, crosslinked povidone SH-SL10 and peppermint essence according to the dosage in a prescription table of a product 6 by using a square cone mixing barrel at a mixing rotating speed of 10rpm for 20min;

Method for measuring and sampling particle size of bulk drug

In a material bag filled with the crushed pregabalin raw material medicines, 5g of each of the upper, middle and lower 6 different positions is sampled respectively, a sample is synthesized after sampling, 30g of the total sample is sampled, and the granularity distribution is detected by inspection.

A microscopic photograph of the drug substance used in product 6 is shown in fig. 8.

Bulk drug and tablet Properties

Experimental results and conclusions

Compared with the bulk drug obtained by sizing with a 0.8mm screen, the difference between D (4, 3) and D (3, 2) of the bulk drug obtained by grinding for 4s with the traditional Chinese medicine grinder is smaller, the D90 is obviously changed to be smaller, and the whole particle size is obviously reduced. The microscopic pictures of the raw materials are combined, so that the pregabalin raw materials obtained by crushing by a traditional Chinese medicine crusher are square crystals and are round, but the whole particle size is smaller, and the D90 is 200 mu m. The tablet result shows that compared with the product 1 of the bulk drug obtained by finishing the screen of 0.8mm, the bulk drug obtained by crushing the bulk drug by a traditional Chinese medicine crusher for 4s has slightly reduced material fluidity, obviously increased friability of the pressed tablet, obviously reduced highest compressible hardness, obviously changed and slow disintegration time limit, is presumed to be that the bulk drug has more fine powder, is easy to adhere to the screen of a disintegration instrument during disintegration, cannot pass smoothly, and leads to longer disintegration time limit. Therefore, the traditional Chinese medicine crushing process is difficult to replace a portal granulating process, the crushing effect of the traditional Chinese medicine crushing process is difficult to control, the control standard is difficult to determine, the pregabalin raw material medicine with specific crystal habit and a certain particle size range cannot be obtained, and the pregabalin orally disintegrating tablet with qualified quality cannot be prepared.

Example 6

Product 7 prescription form:

the preparation process flow of the product 7 comprises the following steps:

(1) crushing pregabalin (D90 is 900 μm, crystal habit is long needle-shaped and square) by a universal crusher, wherein the crushing screen is 0.8mm, the crushing rotating speed is 1500rpm of the minimum rotating speed of equipment, and after crushing, the pregabalin D90 is 250 μm and crystal habit is square;

(2) mixing microcrystalline cellulose, crushed pregabalin, mannitol, sucralose, saccharin sodium, crosslinked povidone SH-SL10 and peppermint essence according to the dosage in a prescription table of a product 7 by using a square cone mixing barrel at a mixing rotating speed of 10rpm for 20min;

Method for measuring and sampling particle size of bulk drug

In a material bag filled with the universal crushed pregabalin bulk drug, 5g of each of the upper, middle and lower 6 different positions is sampled respectively, a sample is synthesized after sampling, 30g of the total sample is sampled, and the granularity distribution is detected by inspection.

A microscopic photograph of the drug substance used in product 7 is shown in fig. 9.

Bulk drug and tablet Properties

Experimental results and conclusions

The grain sizing process of the gate-type grain sizing machine is changed into the grinding of a universal grinder, compared with the raw material medicine obtained by the grain sizing of the gate-type grain sizing machine with a screen of 0.8mm, the difference value between D (4, 3) and D (3, 2) of the raw material medicine obtained by the grinding of the universal grinder is smaller, the D90 is obviously changed to be smaller, and the whole grain size is obviously reduced. The microscopic pictures of the raw materials are combined, so that the pregabalin raw materials obtained by crushing by a universal crusher are square crystals and are round, but the whole particle size is smaller, and D90 is 250 mu m. The tablet results show that compared with the product 1 of the bulk drug obtained by finishing the screen with 0.8mm, the product 7 of the bulk drug obtained by crushing by the universal crusher has slightly increased material fluidity, slightly increased friability of the pressed tablet, slightly reduced highest pressable hardness and obviously changed slow disintegration time limit. Therefore, the universal crushing process is difficult to replace a gate type granule finishing process, the crushing effect of the universal process is difficult to control, the control standard is difficult to determine, the pregabalin bulk drug with specific crystal habit and a certain particle size range cannot be obtained, and the pregabalin orally disintegrating tablet with qualified quality cannot be prepared.

Example 7

Product 8 prescription form:

the preparation process flow of the product 8 comprises the following steps:

(1) dissolving mannitol in water according to a prescription table of a product 8, and uniformly stirring to prepare mannitol solution;

(2) mixing microcrystalline cellulose, pregabalin, sucralose, saccharin sodium, crospovidone SH-SL10 and peppermint essence in a high-shear granulating pot at a shearing rotation speed of 500rpm and a stirring rotation speed of 200rpm for 10min;

(3) spraying mannitol solution into a high-shear granulating pot at a spraying speed of 15g/s and an atomization pressure of 0.08MPa, granulating at a shearing rotating speed of 1500rpm and a stirring rotating speed of 500rpm for 3min;

(4) wet finishing the obtained granule with a size of 8mm, and drying at 45deg.C in a fluidized bed at a fluidization wind speed of 60m ³ Drying, and carrying out door type granule finishing of a screen mesh with the diameter of 0.8mm on the obtained dried granules at the speed of 700rpm;

(5) adding magnesium stearate into the granules after finishing, and mixing by using a square cone mixing barrel at the mixing rotating speed of 10rpm for 20min;

(6) tabletting is carried out by using the mixed granules obtained in the previous step.

Tablet properties

Evaluation of tablet taste

Experimental results and conclusions

The whole powder direct tabletting process is changed into high-shear granulating tabletting, and a tablet result shows that compared with the pregabalin orally disintegrating tablet product 1 obtained by powder direct tabletting, the pregabalin orally disintegrating tablet product 8 obtained by high-shear granulating tabletting has the advantages of small material fluidity change, small friability change of the tabletting agent, slightly reduced maximum pressable hardness, obviously slow disintegration time limit, presumably that the raw material medicine particles are covered by packages after high-shear granulating, are not easy to dissolve and scatter in disintegration, cause the material particles to adhere to a screen of a disintegrating instrument, and can not pass smoothly, and cause longer disintegration time limit. In the taste evaluation results of the tablets of 4 evaluators, the taste caused by the products of different processes is not obviously different, but the taste of the product 8 is evaluated by the 4 evaluators, and the taste is poor, and the taste of the product 1 directly pressed by the powder is better. Therefore, the high-shear granulating and tabletting process is not suitable for preparing the pregabalin orally disintegrating tablet, is also complicated, has lower production efficiency, is difficult to determine the control standard, and is difficult to prepare the pregabalin orally disintegrating tablet with qualified quality.

Example 8

Product 9 prescription form:

the preparation process flow of the product 9 comprises the following steps:

(1) dissolving mannitol in water according to a prescription table of a product 9, and uniformly stirring to prepare mannitol solution;

(2) pregabalin (D90 is 900 μm, crystal habit is long needle-shaped and square) is subjected to granulation by a gate granulator, a 0.8mm granulation screen, and the granulation speed is 700rpm.

(3) Mixing microcrystalline cellulose, pregabalin after finishing, sucralose, saccharin sodium, crosslinked povidone SH-SL10 and peppermint essence in a high-shear granulating pot at a shearing rotating speed of 500rpm and a stirring rotating speed of 200rpm for 10min;

(4) spraying mannitol solution into a high-shear granulating pot at a spraying speed of 15g/s and an atomization pressure of 0.08MPa, granulating at a shearing rotating speed of 1500rpm and a stirring rotating speed of 500rpm for 3min;

(5) wet finishing the obtained granule with a size of 8mm, and drying at 45deg.C in a fluidized bed at a fluidization wind speed of 60m ³ Drying, and carrying out door type granule finishing of a screen mesh with the diameter of 0.8mm on the obtained dried granules at the speed of 700rpm;

(6) adding magnesium stearate into the granules after finishing, and mixing by using a square cone mixing barrel at the mixing rotating speed of 10rpm for 20min;

(7) tabletting is carried out by using the mixed granules obtained in the previous step.

Tablet properties

Experimental results and conclusions

The whole powder direct tabletting process is changed into gate-type granule finishing and then high-shear granulating tabletting, and the tablet result shows that compared with the pregabalin orally disintegrating tablet product 1 obtained by directly tabletting the powder, the material fluidity of the pregabalin orally disintegrating tablet product 9 obtained by gate-type granule finishing and then high-shear granulating tabletting is not greatly changed, the friability of the tabletting is not greatly changed, the highest compressible hardness is not greatly changed, but the disintegration time is still slower, after the high-shear granulating, the particles of the raw material are covered by the package, the particles still are not easily dissolved and dispersed during disintegration, the particles are adhered to the screen of a disintegrating instrument, and the disintegration time is longer. Therefore, the powder direct tabletting process is more suitable for preparing the pregabalin orally disintegrating tablet, the high-shear granulating and tabletting process is also more complicated, the production efficiency is lower, the control standard is difficult to determine, and the pregabalin orally disintegrating tablet with qualified quality is not easy to prepare.

Summary

The grain size of the pregabalin raw material medicines sold in the market at present is about 800-1100 microns, and the crystal habit is mixed crystal of long needle and square crystal. The pregabalin bulk drug has poor compressibility and flowability, and cannot be used for preparing pregabalin orally disintegrating tablets. The preparation method has the advantages that the grain is sized by a gate-type grain sizing machine, the grain sizing screen is 0.8mm, the grain sizing rotating speed is 700rpm, the pregabalin bulk drug with the grain size ranging from 350 to 600 mu m, the difference value range between D (4, 3) and D (3, 2) is smaller, the grain habit is square, and the size ranges from 50 to 150 mu m can be efficiently and easily prepared, so that the fluidity and the compressibility of the pregabalin bulk drug commonly sold on the market at present can be effectively improved, the purposes of simple operation of the production process, mature control standard, low cost, high industrialization degree and excellent quality are achieved. In summary, the invention provides another idea, by preparing the pregabalin raw material medicine with a certain particle size range and a specific crystal habit form, compared with the common pregabalin raw material medicine, the compressibility of the prepared total mixed material is obviously improved, and no extra expensive auxiliary materials are used in the process of preparing the total mixed material.

While the methods of this invention have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations and combinations of the methods and applications described herein can be made and applied within the spirit and scope of the invention. Those skilled in the art can, with the benefit of this disclosure, suitably modify the process parameters to achieve this. It is expressly noted that all such similar substitutions and modifications will be apparent to those skilled in the art, and are deemed to be included within the present invention.

Claims

1. The pregabalin composition suitable for powder tabletting is characterized in that the active component pregabalin is pregabalin with square crystal habit, and the particle size range is D90:500-600 mu m;

the pregabalin composition comprises:

20% -50% of pregabalin;

25.0% -70.0% of filler;

0.1% -15.0% of flavoring agent;

1.0% -20.0% of disintegrating agent;

0.5% -3.0% of lubricant;

the percentages are all percentages by weight of the total prescription;

the filler is microcrystalline cellulose;

the disintegrating agent is crospovidone;

the sum of the dosage of the disintegrating agent and the filling agent is 31 percent.

2. The pregabalin composition of claim 1, characterized in that the difference between pregabalin D (4, 3) and D (3, 2) with square habit is in the range of 50-150 μm.

3. The pregabalin composition of claim 1, wherein the lubricant is at least one of sodium stearyl fumarate, magnesium stearate, colloidal silica, talc.

4. The pregabalin composition of claim 1, wherein the flavoring agent is any one or more of cyclohexylsulfamate, acesulfame potassium, aspartylphenylalanine methyl ester, aspartyl alanine amide, neotame, sucralose, sucrose, sorbitol, mannitol, glucose.

5. The pregabalin composition of claim 1, further comprising a glidant, wherein the glidant is any one or more of aerosil, talc, magnesium stearate.

6. Use of a pregabalin composition of any of the claims 1-5 for the preparation of a pregabalin tablet.

7. A process for preparing pregabalin tablets using the pregabalin composition of claim 1, characterized by the steps of:

(1) Granulating the pregabalin by a gate type granulator, and after granulating, enabling the pregabalin to be the pregabalin with square crystal habit, wherein the particle size range is D90:500-600 mu m;

8. The method of preparing pregabalin tablet of claim 7, where the screen pore size of the granulator is 0.8mm.

9. The process for preparing pregabalin tablet of claim 7, characterized in that the rotational speed of the granulator is 300-700rpm.