WO2023155682A1

WO2023155682A1 - Pregabalin composition suitable for powder tableting and use thereof

Info

Publication number: WO2023155682A1
Application number: PCT/CN2023/074166
Authority: WO
Inventors: 李俊遇; 梁文伟; 刘锋; 谭晓峰
Original assignee: 广州帝奇医药技术有限公司
Priority date: 2022-02-21
Filing date: 2023-02-01
Publication date: 2023-08-24
Also published as: CN114469880A; CN114469880B

Abstract

Provided is a pregabalin composition suitable for powder tableting. The active ingredient pregabalin has a cubic crystal habit, a particle size distribution D90 of 350-600 μm, and a strength of 20%-50% of the weight of the composition. The pregabalin composition further comprises a filler, a disintegrant, a flavoring agent, an essence, and a lubricant. By means of preparing a pregabalin substance with a certain particle size range and a specific crystal habit, compared with conventional pregabalin substances, a blended material with improved compressibility is prepared.

Description

A kind of pregabalin composition suitable for powder compression and application thereof

technical field

The invention belongs to the field of medicine, and in particular relates to a pregabalin composition suitable for powder compression.

Background technique

Internationally, the immediate-release oral solid preparations of pregabalin on the market are tablets, capsules, and orally disintegrating tablets. Compared with ordinary tablets and capsules, orally disintegrating tablets can quickly disintegrate in the oral cavity under the condition of no water or only a small amount of water, especially suitable for the elderly, children, and patients with difficulty swallowing.

Pregabalin or (S)-(+)-3-aminomethyl-5-methyl-hexanoic acid can bind to the α-2-δ (α2δ) subunit of calcium channels and is involved in brain neuronal activity The regulation of related endogenous inhibitory neurotransmitter γ-aminobutyric acid (GABA) is related. As described in U.S. Patent 5,563,175, pregabalin has anti-seizure activity and is indicated for the treatment of epilepsy, pain, physiological disorders associated with psychomotor stimuli, inflammation, gastrointestinal injury, alcoholism, insomnia, Fibromyalgia and various psychiatric disorders including anxiety, depression, mania and bipolar disorder. Pregabalin is approved in the United States for the treatment of diabetic peripheral neuropathy, postherpetic neuralgia, and as an adjunctive treatment for partial-onset seizures in adults. Pregabalin is available as an immediate release (IR) formulation in capsules and administered to patients 2 or 3 times daily (BID or TID). Most patients prefer once-daily dosing to 2 or more daily doses, especially in older patients and patients taking multiple medications, and once-daily dosing is often Patient compliance can be improved. Dosing once a day can also reduce or avoid potential side effects by reducing the maximum concentration of the drug in the blood (CMAX), and can also improve the efficacy of the drug by increasing the minimum concentration in the blood (CMIN).

Oral pharmaceutical compositions containing pregabalin pose significant formulation challenges. Pregabalin drug molecule is a gamma-amino acid (GABA) protein receptor antagonist. After mixing with various excipients, filler excipients such as lactose will accelerate intramolecular cyclization of pregabalin to generate lactam impurities. Pregabalin raw materials are mostly crystalline crystalline particles with poor compressibility, which cannot meet the requirements of conventional powder direct compression or dry granulation. The powder direct compression process is suitable for drugs that are easy to change color and decompose when exposed to moisture or heat. Its most significant advantage is that it reduces the cost of equipment and operation. The material particles for powder direct compression should have good fluidity and compressibility , a certain thickness or crystal form, otherwise it is easy to appear plugging and unqualified product properties during the production process. Therefore improving the compressibility of material is the difficulty of preparing pregabalin orally disintegrating tablet preparation.

Pregabalin is a polymorphic drug, including anhydrous form, hemihydrate form, crystal form I-IV and alpha form. The specific crystalline form combination of a polymorphic drug has an important impact on the physical properties of the product, such as storage, stability, compressibility, bulk density (important in formulation and product manufacturing) and dissolution rate (in determining bioavailability have a significant impact). On the other hand, the characteristic that a crystal grows spontaneously and tends to form a certain shape under certain external conditions is called crystal habit. Crystal habit is the abbreviation of crystal habit, also known as crystal habit, crystal habit, crystal habit, crystal addiction. The classification of crystal habits is usually descriptive, not very strict, and it is difficult to find a clear number of categories and classification standards. The common classification of crystal habits can be divided into layered, dendritic, blade-shaped, needle-shaped, lenticular, and flake according to the appearance of the crystal; according to the angle between the crystal plane and the crystal plane, it can be divided into: prism, pyramid, and plate; according to the polyhedron Divided into: cube, octahedron, dodecahedron; divided into: fibrous, grape-like, radial, massive according to the aggregation state of the single crystal; multiple crystal habits can also exist under one crystal form of the same substance. The physical properties of drug crystal form and crystal habit are very important in drug processing, which may affect the compressibility and fluidity of intermediate products.

CN00812588 provides a method for preparing taste-masked granules of immediate-release drugs, which uses a binder to granulate the mixed powder of active substance, granule disintegrant, penetrant and sweetener, and then uses a coating agent to granulate Taste masking. However, there are many process steps in this method, and the dissolution rate of the product after coating is about 10 percentage points slower than that of the reference preparation (Lyrica) in 5 minutes, so it cannot be released quickly, and the bioavailability is low, and the coated tablet can only be swallowed, not Chewing, the actual taking convenience is not high.

CN103271888 mentions that pregabalin crude drug has poor compressibility, and provides pregabalin medicine (10%-50%), disintegrant crospovidone (5%-30%), microcrystalline cellulose (20% -80%), the rest are prescriptions for flavoring agents, glidants, lubricants; the preparation process is: pregabalin, flavoring agents, microcrystalline cellulose, and disintegrants are mixed in a wet granulator, and an appropriate amount of The water is used for granulation, after granulation, it is dried and sieved, the sieved granules are mixed with the remaining excipients, and the tablets with the required hardness are pressed. Pregabalin powder has poor compressibility, and the pregabalin orally disintegrating tablet developed by the invention overcomes the problem of poor compressibility of pregabalin. The invention found through many tests that the compressibility of the material can be improved through the granulation process, but the product pressed by the material after granulation has obvious taste problems, the taste is gritty, and the disintegration is slow; The finished product prepared by the powder direct pressing process melts in the mouth and has a soft and glutinous taste. Therefore, in order to retain the soft and waxy mouthfeel of pregabalin orally disintegrating tablets, the taste of the product should not be abandoned in order to improve the compressibility of the material by using the granulation process. At the same time, the process steps are relatively complicated, the process of wet granulation requires high energy consumption and takes a long time, and the hot and humid conditions in the processing process will also cause unnecessary stability risks.

CN111096953 provides a pregabalin orally disintegrating tablet using silicified microcrystalline cellulose powder that can be directly compressed into tablets and its preparation method. It premixes pregabalin and silicified microcrystalline cellulose, then mixes it with other auxiliary materials, and then performs powder direct compression. Its prescription ratio is pregabalin drug (10%-30%), disintegrant crospovidone (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 the material so that the prepared orally disintegrating tablet has excellent stability. But silicified microcrystalline cellulose is a relatively expensive auxiliary material, its price is 3 to 4 times that of general microcrystalline cellulose, and the prescription dosage of microcrystalline cellulose is 20% to 40%, the increase of its cost will Not conducive to product marketing.

Generally, improving the compressibility of pregabalin orally disintegrating tablets can be considered by adding excipients with better compressibility or reducing the proportion of pregabalin in the prescription, but this will increase the tablet weight and size problems, and also reduce the number of tablets produced in a single batch. The way of increasing the binder will affect the disintegration behavior of the product and prolong the disintegration time of the product. The wet granulation method can effectively improve the compressibility of the granules, but such a process will increase the cost of processing and time in the preparation, and at the same time, exposure to damp and heat factors will increase the risk of product impurities. At present, most methods to improve the compressibility of pregabalin orally disintegrating tablets are by adding excipients with better compressibility or performing wet granulation. These methods will increase the cost of the product and affect the disintegration time limit of the product situation etc.

Contents of the invention

Purpose of the invention: the technical problem to be solved by this invention is to provide a kind of pregabalin composition suitable for powder compression for the deficiencies of the prior art. Compounding with additives, lubricants and disintegrants can significantly improve the compressibility of materials, and through a simple mixing and tableting process, pregabalin orally disintegrating tablets of good quality can be produced.

In order to solve the above technical problems, the present invention discloses a pregabalin composition suitable for powder compression, the active component pregabalin is pregabalin with a square crystal habit, and the particle size range is D90: 350-600 μm , the dosage accounts for 20%-50% of the total weight of the prescription.

The pregabalin composition also includes fillers, disintegrants, flavoring agents, essences and lubricants.

Specifically, the dosage of the filler is 0.0% to 80.0%, the flavoring agent is 0.1% to 15.0%, the disintegrant is 1.0% to 20.0%, the lubricant is 0.5% to 3.0%, preferably, the dosage of the filler is 30.0% ～70.0%, flavoring agent 1.0%～5.0%, disintegrant 1.0%～10.0%, lubricant 0.5%～3.0%, glidant 0.1%～1.0%, the above percentages are the percentages of the total weight of the prescription.

Wherein, the filler is any one or both of cellulose derivatives and starch derivatives. further, The filler is such as cyclodextrin, dextrin, microcrystalline cellulose, pregelatinized starch, sodium carboxymethyl starch, mannitol, sorbitol, xylitol, glucose, methylcellulose, hydroxypropyl starch etc.; preferably, the filler is at least one of microcrystalline cellulose, calcium hydrogen phosphate dihydrate, mannitol or lactose.

The disintegrant is at least one of croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose or sodium carboxymethyl starch; the glidant is micropowder silica gel, talc Any one or more of powder, magnesium stearate.

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

Described corrective agent is cyclamate (cyclamate), acesulfame potassium (acesulfame potassium, A-K sugar), aspartame (aspartame, sweetener) , aspartame (alitame), neotame, sucralose, sucrose, sorbitol, mannitol, glucose in any one or more; the flavor is a natural flavor or a synthetic flavor, It preferably includes at least one of milk flavor, grape flavor, strawberry flavor, vanillin, apple flavor, orange flavor, banana flavor, orange oil and other natural or artificial flavors.

The composition also includes a glidant, and the amount of the glidant accounts for 0.1-1.0% of the total mass of the prescription. The glidant is any one or more of micropowder silica gel, talcum powder, and magnesium stearate. .

The present invention further proposes the application of the above pregabalin composition in the preparation of pregabalin tablets.

Further, the present invention proposes a preparation method of pregabalin tablet, comprising the steps of:

(1) Carry out the granulation of each raw material drug by a door-type granulator, and carry out granulation of each raw material drug by a door-type granulator. After the granulation, pregabalin is pregabalin with a square crystal habit, and the particle size range is D90: 350～600μm;

(2) mixing each raw and auxiliary material except the lubricant, sieving, adding the lubricant and mixing to obtain mixed granules;

(3) Compress the mixed granules through a tablet machine to obtain plain tablets with a hardness of 4-6kg.

Preferably, the sieve aperture of the granulator is 0.8mm, and the granulation speed is 300-700rpm. The tablet prepared by the invention can be used as an immediate-release preparation for treating epilepsy and neuropathic pain.

Beneficial effect: compared with the prior art, the present invention has the following advantages:

(1) The present invention has obtained through a large number of experiments and researches by the inventors: the pregabalin bulk drug with a particle size range D90 of 350 to 600 μm and a square crystal habit is compounded with fillers, lubricants and disintegrants, The compressibility of materials can be significantly improved, and pregabalin orally disintegrating tablets of good quality can be prepared through a simple mixing and tableting process. The rapid-release preparation can realize the rapid release of the active ingredient pregabalin, so that the effective blood drug concentration can be reached more quickly after oral administration; compared with the traditional capsule preparation, the prepared rapid-release preparation of the present invention has fast onset of action, fast absorption, and stable The effect, the taste is cool and slightly Sweet, melt-in-the-mouth, soft and glutinous taste, no unbearable bitterness, can improve patient compliance.

(2) The preparation method of the present invention uses a door-type granulator to process the pregabalin bulk drug to obtain the pregabalin bulk drug with a specific crystal habit and a certain particle size range, and then by mixing with various conventional auxiliary materials, A material granule with excellent compressibility is prepared by a relatively simple process for preparing orally disintegrating pregabalin tablets. The process has the advantages of simple operation, mature control standard, low cost and high degree of industrialization;

(3) The present invention finds that the melting point of lipid excipients is relatively low by conducting stability research experiments on reference preparations, which will affect the changes in product quality indicators during the stability investigation process, such as appearance, related substances, dissolution, hardness, etc. , and the use of these higher-priced accessories will also increase product costs. The present invention simplifies the types of auxiliary materials and controls the particle size and crystal habit of the pregabalin crude drug, so as to reduce the product cost and prepare the stable pregabalin quick-release preparation.

Description of drawings

The advantages of the above and/or other aspects of the present invention will become clearer as the present invention will be further described in detail in conjunction with the accompanying drawings and specific embodiments.

Fig. 1 is the microscopic picture of the bulk drug used in product 1;

Fig. 2 is the microscopic picture of the bulk drug used in product 2;

Fig. 3 is a picture of the particle size distribution of the bulk drug used in product 1;

Fig. 4 is the particle size distribution picture of the raw material drug used in product 2;

Fig. 5 is a microscope picture of the raw material drug used in product 3;

Fig. 6 is a microscope picture of the bulk drug used in product 4;

Fig. 7 is a microscope picture of the raw material drug used in product 5;

Fig. 8 is a microscope picture of the bulk drug used in product 6;

Fig. 9 is a microscope picture of the bulk drug used in product 7;

Figure 10 is a picture of the dissolution curves of Product 1, Product 2 and the reference preparation.

Detailed ways

In order to better understand the present invention, the present invention and its advantages and beneficial effects will be discussed through the following examples and experimental data of the present invention.

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

Sampling method for particle size determination of raw materials:

In the material bag containing the granulated pregabalin raw material drug, 5g samples were taken from 6 different positions at the top, middle and bottom respectively. After sampling, a sample was synthesized, and a total of 30g was sampled, which was sent for inspection for particle size distribution.

Method for measuring the particle size of raw materials:

Method for measuring the particle size of the raw material: Weigh about 0.3g of the dispersant Span-85 into a 250ml beaker, then add an accurately measured 120ml of n-heptane to obtain a certain proportion of Span-85 n-heptane solution, and place it in a trace In the disperser, stir until the background is stable, measure the background signal, then add 0.1g pregabalin sample, stir for 60s to obtain a certain concentration of the sample to be tested, place the sample in the micro-wet sampling window of the laser particle size analyzer, and Run the corresponding measurement method file according to the relevant parameter items, and take the arithmetic mean value of the three measurement results to obtain the particle size data of the raw material drug.

Analysis of raw material particle size data:

The meaning of particle size distribution is to use specific instruments and methods to measure the percentage of particles of different particle sizes in the powder sample to the total particle volume (or number, etc.). D10: The accumulation of a sample (add the percentage of all particle sizes in front or behind), the corresponding particle size when the particle size distribution number reaches 10%. Its physical meaning is that the particles whose particle size is smaller (or larger) account for 10%. D90: The particle size corresponding to when the cumulative particle size distribution number of a sample reaches 90%. Its physical meaning is that the particles whose particle size is smaller (or larger) account for 90%. D50: The particle size corresponding to when the cumulative particle size distribution percentage of a sample reaches 50%. Its physical meaning is that the particles with a particle size larger than it account for 50%, and the particles smaller than it also account for 50%. D50 is also called the median diameter or median particle diameter. It does not indicate the average particle size of the powder, but indicates that the average particle size of the powder has other parameters, such as D(4,3), D(3,2) and so on. Both D(4,3) and D(3,2) represent the average particle diameter on the basis of volume. The full name of D(4,3) is "mass moment volume average particle diameter" and is referred to as volume average diameter for short. The calculation method is to average the particle size values at both ends of each particle size range, multiply the particle size distribution percentage corresponding to this range, and then accumulate the products, that is, D(4,3)=f1·D1+f2·D2 +f3·D3+…. The full name of D(3,2) is "volume area average particle diameter", and it is referred to as area average diameter for short. The calculation method is to divide the percentage of each particle size range by the average value of its corresponding particle size range, add up, and then calculate the reciprocal, that is, D(3,2)=1÷(f1÷D1+f2÷D2+f3÷D3+ ...). Among them: Di represents the average particle size of the i-th particle size interval, and fi represents the i-th one. The relationship between D(3,2) and D(4,3) can be understood as follows: for laser particle size analyzers, the closer to spherical particles, the more accurate the measurement results. Then, when the values of D(3,2) and D(4,3) are closer, it means that the shape of the sample particles is more regular and the particle size distribution is more concentrated. The larger the difference, the more irregular the shape of the sample particles and the wider the particle size distribution.

Microscopic observation method of API crystals:

The crystal habit appearance of raw materials is observed and measured through a microscope. Take 0.01g of pregabalin bulk drug on the glass slide On, drop 1 drop of liquid paraffin to disperse. The microscope eyepiece parameter is 10 times, and the objective lens parameter is 5 times. Observe and take pictures with uniform dispersion of particles and sufficient light.

Determination methods for fluidity, tablet friability and maximum tablet hardness:

Take 100g of the blended material and use the FT-104B angle of repose tester to measure the fluidity of the material. Take about 6.5g of the finished product and use the CJY-300D tablet friability tester to measure the tablet friability. Use the YPD-200C tablet hardness tester to measure the hardness of the finished tablet.

Example 1

Product 1 Prescription Form:

Product 2 Prescription Form:

Product 1 preparation process:

① Pregabalin (D90 is 900 μm, crystal habit is long needle-shaped and square) is sized by a door-type granulator with a 0.8 mm sieve, and the granulation speed is 700 rpm. After sizing, the D90 of pregabalin is 500 μm , The crystal habit is square;

②According to the dosage in the prescription table of product 1, mix microcrystalline cellulose, granulated pregabalin, mannitol, sucralose, sodium saccharin, crospovidone SH-SL10, and mint flavor in a square cone mixing bucket Mixing, mixing speed 10rpm, mixing time 20min;

③ Pass the mixed granules obtained in the previous step through a 20-mesh vibrating sieve, and then add magnesium stearate to the granules after sieving, and use a square cone mixing barrel for mixing, the mixing speed is 10 rpm, and the mixing time is 20 minutes;

④ Use the mixed granules obtained in the previous step for direct powder compression.

Product 2 preparation process:

①According to the dosage in the prescription table of product 2, pregabalin (D90 is 900 μm, crystal habit is long needle-shaped and square), microcrystalline cellulose, mannitol, sucralose, sodium saccharin, crospovidone SH-SL10 and mint essence are mixed in a square cone mixing barrel, the mixing speed is 10rpm, and the mixing time is 20min;

② Pass the mixed granules obtained in the previous step through a 20-mesh vibrating sieve, and then add magnesium stearate to the granules after sieving and use a square cone mixing barrel for mixing, the mixing speed is 10 rpm, and the mixing time is 20 minutes;

③ Use the mixed granules obtained in the previous step for direct powder compression.

The microscope images of the raw materials used in product 1 and product 2 are shown in Figure 1 and Figure 2, respectively, and the particle size distributions of the raw materials used in product 1 and product 2 are shown in Figure 3 and Figure 4, respectively.

API and Tablet Properties

Experimental Results and Conclusion

The D90 of the API of product 1 after being granulated by the portal granulator is 500 μm, and the difference between D(4,3) and D(3,2) is 74 μm. The D90 of product 2 API is 900 μm, and the difference between D(4,3) and D(3,2) is 575 μm. Compared with product 2, the difference between product 1 API D(3,2) and D(4,3) is smaller, indicating that the shape of product 1 API particles is more regular, and the particle size distribution is concentrated. According to its microscopic photos, it shows that its The crystal habit is square crystal. The difference between D(3,2) and D(4,3) of product 2 raw material drug is large, indicating that the shape of product 2 raw material drug particle is irregular and the particle size distribution is wide, and according to its microscopic photo, it shows that its crystal habit is not uniform The square crystal and long needle crystal mixed crystal.

Tablet results show that the crystal habit is mainly square crystal, and the product 1 whose D90 is 500 μm is more than the product 2 whose crystal habit is mainly long needle-like crystal and square crystal mixed crystal in the raw material medicine, and its material fluidity is better, and the pressed tablet is brittle The degree is lower and the maximum compressive hardness is higher. Therefore, the use of pregabalin raw materials whose crystal habit is mainly fang crystal can effectively improve the fluidity and compressibility of the material, and prepare pregabalin orally disintegrating tablets with excellent properties.

Fig. 10 is the dissolution curve chart of product 1 and product 2 and reference preparation. The 0.06M HCL-paddle method is used for detection, and the specific detection steps are:

Dissolution medium: 0.06M hydrochloric acid solution, preparation steps: Measure 5.4ml of hydrochloric acid, dilute with water to 1000ml, shake well, and get ready.

Control solution: take about 16 mg of pregabalin reference substance, accurately weigh it, place it in a 100 mL volumetric flask, add dissolution medium to dissolve and quantitatively dilute to the mark, shake well (concentration is about 160 μg/ml). Prepare two copies in parallel.

Mobile phase preparation:

(1) 0.04M diammonium hydrogen phosphate (pH6.5)

Accurately weigh 5.28g of diammonium hydrogen phosphate + ultrapure water, set the volume to 1000ml, adjust the pH value to 6.5±0.05 with phosphoric acid, and filter with suction.

(2) Mobile phase: 0.04M diammonium hydrogen phosphate (pH6.5): acetonitrile = 90:10

Dissolution conditions:

Dissolution medium: 0.06M hydrochloric acid

Dissolution Apparatus: Paddle Method

Speed: 50rpm

Dissolution medium temperature: 37±0.5℃

Sampling volume, rehydration volume: sampling 3.5ml, discarding 2ml of waste liquid, no rehydration.

Dissolution medium volume: 900ml.

Sampling method: Random sampling.

Sample solution treatment: use a 0.45 μm water filter head (Jinteng, polyethersulfone, 25mm) to filter, discard 2ml of the initial filtrate, and take the subsequent filtrate as the sample solution.

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

High performance liquid chromatography detection conditions:

Column: GL Sciences Inertsil ODS-3V.

The preparation is pregabalin orally disintegrating tablets. The pregabalin was first listed in Japan on February 17, 2017. The English product name is LYRICA (Lerica), and the Japanese product name is リリカOD Tablet. The licensee is Pfizer Japan Inc. (ファイザー Co., Ltd.), the reference preparation is marked as EA6596 in this application. As can be seen from the results, the stripping curve of the product of the present invention is similar to that of the reference preparation, and the in vitro results illustrate to a certain extent that the product of the present invention has the same rapid onset and absorption as the reference preparation.

Example 2

Product 3 Prescription Form:

Product 3 preparation process:

① Pregabalin (D90 is 900 μm, crystal habit is long needle-shaped and square) is sized by a door-type granulator with a 0.8mm sieve, and the granulation speed is reduced from 700rpm to 300rpm, which is the lowest speed of the equipment. The D90 of pregabalin is 550 μm, and the crystal habit is square;

②According to the dosage in the prescription table of product 3, mix microcrystalline cellulose, granulated pregabalin, mannitol, sucralose, sodium saccharin, crospovidone SH-SL10, and mint essence in a square cone mixing bucket. Mixing, mixing speed 10rpm, mixing time 20min;

The microscope picture of the API used in product 3 is shown in Figure 5.

API and Tablet Properties

Experimental Results and Conclusion

The door-type granulator speed is reduced from 700rpm to 300rpm, compared with the bulk drug obtained at the 700rpm granulation speed, the D90 of the raw material drug obtained at the 300rpm granulation speed, the difference between D (4, 3) and D (3, 2) has no difference. obvious change. Tablet results show that, compared with product 1 obtained by granulating at 700rpm, there is no significant difference in material fluidity, friability and maximum compressible hardness of product 3 obtained at 300rpm. . Therefore, 700rpm, which has higher production efficiency, should be used as the granulation speed parameter of the gantry granulator in the subsequent production process, which is simple and easy to control.

Example 3

Product 4 Prescription Form:

Product 4 preparation process:

① Pregabalin (D90 is 900 μm, crystal habit is long needle-shaped and square) is sized by a door-type granulator, the 0.8mm sieve is changed to a 0.9mm sieve, and the sizing speed is 700rpm. After sizing, The D90 of pregabalin is 700 μm, and the crystal habit is long needle-shaped and square.

②Mix the microcrystalline cellulose, granulated pregabalin, mannitol, sucralose, sodium saccharin, crospovidone SH-SL10, and mint essence in a square cone mixing barrel according to the dosage in the product 4 prescription table , mixing speed 10rpm, mixing time 20min;

The microscope picture of the API used in product 4 is shown in Figure 6.

API and Tablet Properties

Experimental Results and Conclusion

Replace the 0.8mm sieve mesh of the gate granulator with a 0.9mm sieve, compared with the bulk drug obtained by 0.9mm sieve sizing, the D90, D (4, 3) and The differences of D(3, 2) all increased significantly. Combined with the microscope pictures of the raw material drug, it shows that the pregabalin raw material drug obtained by 0.9mm sieve granulation is long needle-shaped crystal and square crystal mixed crystal, which is not as round as the raw material drug obtained by 0.8mm sieve granulation, and the overall particle size is too large. D90 is 700 μm. Tablet results show that compared with the product 1 of the raw material drug obtained by 0.8 mm sieve granulation, the material fluidity of product 4 of the raw material drug obtained by 0.9 mm sieve granulation slows down, and the friability of the pressed tablet becomes higher. The maximum compressible hardness decreased, and the disintegration time became slower. Therefore, the 0.8mm screen should be used as the screen parameter of the portal granulator in the subsequent production process. The operation is simple and easy to control, and the product quality can be guaranteed.

Example 4

Product 5 Prescription Form:

Product 5 preparation process:

① Pregabalin (D90 is 900 μm, crystal habit is long needle-shaped and square) is sized by a door-type granulator, the 0.8mm granulation screen is changed to a 0.7mm sieve, and the granulation speed is 700rpm. Pregabalin D90 is 350 μm, and the crystal habit is square;

②According to the dosage in the prescription table of product 5, mix microcrystalline cellulose, granulated pregabalin, mannitol, sucralose, sodium saccharin, crospovidone SH-SL10, and mint essence in a square cone mixing bucket Mixing, mixing speed 10rpm, mixing time 20min;

The microscope picture of the API used in product 5 is shown in Figure 7.

API and Tablet Properties

Experimental Results and Conclusion

Replace the 0.8mm sieve mesh of the portal granulator with a 0.7mm sieve, compared with the raw material medicine obtained by 0.8mm sieve sizing, the D(4, 3) and D( 3, 2) The difference has no obvious change, but the D90 is obviously smaller, and the overall particle size is obviously smaller. Combined with the microscope pictures of the raw material drug, it shows that the pregabalin raw material drug obtained by 0.7mm sieve granulation is a square crystal, which is relatively round, but the overall particle size is relatively small, and the D90 is 350 μm. Tablet results show that compared with Product 1 of the bulk drug obtained through 0.8 mm sieve granulation, the material fluidity of Product 5 of the bulk drug obtained through 0.7 mm sieve granulation has no significant change, and the friability of the pressed tablet is slightly reduced. increased, the maximum compressible hardness decreased slightly, and the disintegration time limit was significantly slower. It is speculated that there are more fine powders of raw materials, which tend to adhere to the disintegration instrument screen during disintegration and cannot pass through smoothly, resulting in a longer disintegration time limit. Therefore, the 0.8mm screen should be used as the screen parameter of the portal granulator in the subsequent production process. The operation is simple and easy to control, and the product quality can be guaranteed.

Example 5

Product 6 Prescription Form:

Product 6 preparation process:

① Pulverize pregabalin (with a D90 of 900 μm and a long needle-like crystal habit and a square shape) in a traditional Chinese medicine pulverizer for 4 s, and the obtained pregabalin has a D90 of 200 μm and a square crystal habit;

② Mix microcrystalline cellulose, pulverized pregabalin, mannitol, sucralose, sodium saccharin, crospovidone SH-SL10, and mint essence in a square cone mixing barrel according to the dosage in the product 6 prescription table. Mixing speed 10rpm, mixing time 20min;

Sampling method for particle size determination of raw materials

In the material bag containing the pregabalin crude drug after crushing the traditional Chinese medicine, 5g samples were taken from 6 different positions at the top, middle and bottom respectively. After sampling, a sample was synthesized, and a total of 30g was sampled, which was sent for inspection for particle size distribution.

The microscope picture of the API used in Product 6 is shown in Figure 8.

API and Tablet Properties

Experimental Results and Conclusion

The granulation process of the portal granulator was changed to pulverization by the traditional Chinese medicine pulverizer. Compared with the raw material medicine obtained by 0.8mm sieve granulation, the D (4, 3) and D (3, 2) of the raw material medicine obtained by pulverizing the traditional Chinese medicine pulverizer for 4 seconds The difference is smaller, and the D90 is significantly smaller, and the overall particle size is significantly smaller. Combined with the microscope pictures of the raw material drug, it shows that the pregabalin raw material drug obtained by pulverizing the traditional Chinese medicine pulverizer is a square crystal, which is relatively round, but the overall particle size is relatively small, and the D90 is 200 μm. Tablet results show that, compared with product 1 of the raw material drug obtained by 0.8mm sieve granulation, the material fluidity of product 6 of the raw material drug obtained by pulverizing the traditional Chinese medicine pulverizer for 4 seconds is slightly reduced, and the friability of the pressed tablet is significantly increased, the highest The compressible hardness decreased significantly, and the disintegration time limit changed significantly. Slower, it is speculated that there are more fine powders of raw materials, which tend to adhere to the screen of the disintegration instrument during disintegration, and cannot pass through smoothly, resulting in a longer disintegration time limit. Therefore, it is difficult for traditional Chinese medicine pulverization process to replace the door-type granulation process. The pulverization effect of traditional Chinese medicine pulverization process is difficult to control, and the control standard is difficult to determine. Oral disintegration of pregabalin.

Example 6

Product 7 Prescription Form:

Product 7 preparation process:

① Pulverize pregabalin (D90 is 900 μm, and the crystal habit is long needle-shaped and square) in a universal pulverizer. habit of square;

② Mix microcrystalline cellulose, pulverized pregabalin, mannitol, sucralose, sodium saccharin, crospovidone SH-SL10, and mint essence in a square cone mixing tank according to the dosage in the product 7 prescription table, Mixing speed 10rpm, mixing time 20min;

Sampling method for particle size determination of raw materials

In the material bag containing the pregabalin raw material after universal crushing, 5g samples were taken from 6 different positions at the top, middle and bottom respectively. After sampling, a sample was synthesized, and a total of 30g was sampled, which was sent for inspection for particle size distribution.

The microscope picture of the API used in Product 7 is shown in Figure 9.

API and Tablet Properties

Experimental Results and Conclusion

The granulation process of the portal granulator is changed to the pulverization of the universal pulverizer. Compared with the raw material medicine obtained by the 0.8mm screen gantry granulator, the D (4, 3) and D ( 3, 2) The difference is smaller, and the D90 is significantly smaller, and the overall particle size is significantly smaller. Combined with the microscope pictures of the raw material drug, it shows that the pregabalin raw material drug obtained by pulverizing with a universal pulverizer is a square crystal, which is relatively round, but the overall particle size is relatively small, and the D90 is 250 μm. Tablet results show that compared with the product 1 of the raw material drug obtained by 0.8mm sieve granulation, the material fluidity of the product 7 of the raw material drug obtained by pulverizing the universal pulverizer slightly decreases, and the friability of the pressed tablet increases slightly, the highest The compressible hardness decreased slightly, and the disintegration time was significantly slower. Therefore, it is also difficult for the universal pulverization process to replace the door-type granulation process. The pulverization effect of the universal process is also difficult to control, and the control standards are difficult to determine. It is impossible to obtain pregabalin raw materials with specific crystal habits and a certain particle size range, and the preparation quality is not qualified. orally disintegrating pregabalin tablets.

Example 7

Product 8 Prescription Form:

Product 8 preparation process:

① Dissolve mannitol in water according to the prescription table of product 8, and stir evenly to prepare mannitol solution;

②Mix microcrystalline cellulose, pregabalin, sucralose, sodium saccharin, crospovidone SH-SL10, and mint essence in a high-shear granulator, with a shear speed of 500 rpm and a stirring speed of 200 rpm, and mix Time 10min;

③Spray the mannitol solution into a high-shear granulation pot with a spray speed of 15g/s and an atomization pressure of 0.08MPa for granulation. The shear speed is 1500rpm, the stirring speed is 500rpm, and the granulation time is 3min;

④The prepared granules are subjected to 8*8mm wet granulation, and then dried in a fluidized bed at a drying temperature of 45°C and a fluidization wind speed of 60m ³ /h, and the obtained dried granules are then subjected to 0.8mm sieve gate type granulation , the rotation speed of the whole grain is 700rpm;

⑤After granulation, add magnesium stearate to the granules and use a square cone mixing barrel for mixing, the mixing speed is 10rpm, and the mixing time is 20min;

⑥Use the mixed granules obtained in the previous step for tablet compression.

Tablet properties

Tablet taste evaluation

Experimental Results and Conclusion

The overall powder direct compression process was changed to high-shear granulation tablet compression. Tablet results showed that compared with the pregabalin orally disintegrating tablet product 1 obtained by powder direct compression, the pregabalin obtained by high-shear granulation Orally disintegrating tablet product 8 has little change in material fluidity, little change in the friability of the compressed tablet, a slight decrease in the maximum compressible hardness, and a significantly slower disintegration time limit, which is presumed to be the raw material medicine after high-shear granulation The particles are wrapped and covered, and it is not easy to dissolve and disperse during disintegration, which causes the material particles to adhere to the screen of the disintegration instrument and cannot pass through smoothly, resulting in a longer disintegration time limit. In the tablet mouthfeel evaluation results of the 4 evaluators, there was no significant difference in the taste caused by the products of different processes, but the taste evaluation of the product 8 by the 4 evaluators all reflected that the mouthfeel was not good, there were fine grains, etc., and the overall In terms of taste, the taste of product 1 directly compressed by powder is better. Therefore, the high-shear granulation tableting process is not suitable for the preparation of pregabalin mouth-disintegrating tablets. The high-shear granulation tableting process is also relatively cumbersome, the production efficiency is low, the control standard is difficult to determine, and it is difficult to obtain qualified quality tablets. Oral disintegration of pregabalin.

Example 8

Product 9 Prescription Form:

Product 9 preparation process:

① Dissolve mannitol in water according to product 9 prescription table, and stir evenly to make mannitol solution;

② Pregabalin (D90 is 900 μm, crystal habit is long needle-shaped and square) is sized by a portal granulator with a 0.8mm sieve at a sizing speed of 700rpm.

③Mix microcrystalline cellulose, pregabalin after granulation, sucralose, sodium saccharin, crospovidone SH-SL10, and mint essence in a high-shear granulator, with a shearing speed of 500 rpm and a stirring speed of 500 rpm. 200rpm, mixing time 10min;

④ Spray the mannitol solution into a high-shear granulation pot with a spray speed of 15g/s and an atomization pressure of 0.08MPa for granulation. The shear speed is 1500rpm, the stirring speed is 500rpm, and the granulation time is 3min;

⑤The prepared granules are subjected to 8*8mm wet granulation, and then dried in a fluidized bed at a drying temperature of 45°C and a fluidization wind speed of 60m ³ /h, and the obtained dried granules are then subjected to 0.8mm sieve gate type granulation , the rotation speed of the whole grain is 700rpm;

⑥After granulation, add magnesium stearate to the granules and use a square cone mixing barrel for mixing, the mixing speed is 10rpm, and the mixing time is 20min;

⑦Use the mixed granules obtained in the previous step for tablet compression.

Tablet properties

Experimental Results and Conclusion

The powder direct compression process was changed as a whole to gate-type granulation of the raw material drug first, and then high-shear granulation and tablet compression. The tablet results showed that compared with the pregabalin orally disintegrating tablet product 1 obtained by powder direct compression, The material fluidity of the pregabalin mouth-disintegrating tablet product 9 obtained by gate-type granulation of the raw material drug and then high-shear granulation and tablet compression did not change much, the friability of the compressed tablet did not change much, and the highest compressible hardness There is little change, but the disintegration time limit is still relatively slow. It is speculated that after high-shear granulation, the raw material drug particles are covered after gate-type granulation. The disintegration instrument screen cannot pass through smoothly, resulting in a longer disintegration time limit. Therefore, the powder direct compression process is more suitable for the preparation of pregabalin orally disintegrating tablets, and the high-shear granulation tableting process is also relatively cumbersome, the production efficiency is low, the control standard is difficult to determine, and it is difficult to obtain qualified pregabalin Mouth disintegration.

Summarize

At present, the particle size range of common pregabalin raw materials sold in the market is about 800-1100 microns, and the crystal habit is elongated needle-shaped and square crystal mixed crystal. This pregabalin crude drug has poor compressibility and fluidity, and cannot be used for the preparation of pregabalin orally disintegrating tablets. The granulation is sized by a door-type granulator, the size of the sieve is 0.8mm, and the granulation speed is 700rpm, which can efficiently and easily control the preparation of particle sizes ranging from 350 to 600μm, D(4,3) and D(3, 2) The range of the difference is small, 50-150 μm, pregabalin API with square crystal habit, this API can effectively improve the fluidity and compressibility of common pregabalin APIs currently on the market, The purpose of producing pregabalin orally disintegrating tablets with simple operation, mature control standards, low cost, high industrialization degree and excellent quality is achieved. In summary, the present invention provides another way of thinking, by preparing pregabalin raw materials with a certain particle size range and specific crystal habit, compared with ordinary pregabalin raw materials, the compressibility of the prepared blended materials Significantly improved, and no additional costly excipients are used in the preparation of the blend.

The method of the present invention has been described through preferred embodiments, and relevant persons can obviously make changes or appropriate changes and combinations to the methods and applications described herein within the content, spirit and scope of the present invention to realize and apply the technology of the present invention . Those skilled in the art can refer to the content of this article to appropriately improve the process parameters to achieve. In particular, it should be pointed out that all similar substitutions and modifications are obvious to those skilled in the art, and they are all considered to be included in the present invention.

Claims

A pregabalin composition suitable for powder compression, characterized in that the active component pregabalin is pregabalin with a square crystal habit, the particle size range is D90: 350-600 μm, and the dosage accounts for the total weight of the prescription 20%-50% of.
The pregabalin composition according to claim 1, wherein the pregabalin composition also includes a filler, a disintegrating agent, a flavoring agent, an essence and a lubricant.
The pregabalin composition according to claim 2, wherein the dosage of the filler is 0.0% to 80.0%, the flavoring agent is 0.1% to 15.0%, the disintegrant is 1.0% to 20.0%, and the lubricant is 0.5%. %～3.0%, the above percentages are the percentages of the total weight of the prescription.
The pregabalin composition according to claim 2, wherein the filler is any one or both of cellulose derivatives and starch derivatives.
The pregabalin composition according to claim 2, wherein the disintegrant is croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose or carboxymethyl starch at least one of sodium.
The pregabalin composition according to claim 2, wherein the lubricant is at least one of sodium stearyl fumarate, magnesium stearate, micronized silica gel, and talcum powder.
The pregabalin composition according to claim 2, wherein the flavoring agent is cyclamate, acesulfame potassium, aspartame, aspartame Any one or more of amino acid amide, neotame, sucralose, sucrose, sorbitol, mannitol, and glucose; the flavor is a natural flavor or an artificial flavor.
The pregabalin composition according to claim 2, is characterized in that, also comprises glidant, and described glidant is any one or more in micropowder silica gel, talcum powder, magnesium stearate.
Application of the pregabalin composition described in any one of claims 1-8 in the preparation of pregabalin tablets.
A preparation method of pregabalin tablet, is characterized in that, comprises the steps:

(1) Carrying out the granulation of each bulk drug by a door-type granulator, after granulation, the pregabalin is pregabalin with a square crystal habit, and the particle size range is D90: 350-600 μm;

(2) mixing each raw and auxiliary material except the lubricant, sieving, adding the lubricant and mixing to obtain mixed granules;

(3) Compress the mixed granules through a tablet machine to obtain plain tablets with a hardness of 4-6kg.