CN114469880A - Pregabalin composition suitable for powder tabletting and application thereof - Google Patents
Pregabalin composition suitable for powder tabletting and application thereof Download PDFInfo
- Publication number
- CN114469880A CN114469880A CN202210155830.6A CN202210155830A CN114469880A CN 114469880 A CN114469880 A CN 114469880A CN 202210155830 A CN202210155830 A CN 202210155830A CN 114469880 A CN114469880 A CN 114469880A
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- Prior art keywords
- pregabalin
- product
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- raw material
- tablet
- Prior art date
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- 229960001233 pregabalin Drugs 0.000 title claims abstract description 127
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- A—HUMAN NECESSITIES
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- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid, pantothenic acid
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- A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
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Abstract
The invention discloses a pregabalin composition suitable for powder tabletting, wherein the pregabalin as an active component is pregabalin with square crystal habit, the particle size range is D90: 350-600 mu m, and the dosage of the pregabalin composition accounts for 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 compared with the common pregabalin bulk drug, the prepared bulk drug has obviously improved compressibility and reduced production cost by preparing the pregabalin bulk drug with a certain particle size range and a specific crystal habit form.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to a pregabalin composition suitable for powder tabletting.
Background
The marketed immediate-release oral solid preparation of pregabalin is tablet, capsule and oral disintegrating tablet internationally. Compared with common tablets and capsules, the orally disintegrating tablet can be rapidly disintegrated in the oral cavity under the condition of no water or only a small amount of water, and is particularly suitable for the old, children and patients with dysphagia.
Pregabalin or (S) - (+) -3-aminomethyl-5-methyl-hexanoic acid can bind to the α -2- δ (α 2 δ) subunit of calcium channels and are involved in the endogenous inhibitory neurotransmitter γ -aminobutyric acid (GABA) associated with the regulation of neuronal activity in the brain. As described in U.S. patent No. 5,563,175, pregabalin has anti-seizure activity and is useful for the treatment of the following conditions: 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 has been approved in the united states for the treatment of diabetic peripheral neuropathy, post-herpetic neuralgia, and as an adjunct treatment in 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 prefer to take the drug once a day as compared to 2 or more administrations per day, especially for elderly patients and patients taking multiple drugs, and an administration regimen of 1 time a day may generally improve patient compliance. Once daily administration may also reduce or avoid potential side effects by reducing the maximum concentration of the drug in the blood (CMAX) and may also improve drug efficacy by increasing the minimum concentration in the blood (CMIN).
Oral pharmaceutical compositions containing pregabalin present significant formulation challenges. The pregabalin drug molecule is an antagonist of gamma-amino acid (GABA) protein receptors. After being mixed with various auxiliary materials, the filler auxiliary materials such as lactose can accelerate the intramolecular cyclization of the pregabalin to generate lactam impurities. Most of the pregabalin bulk drugs are crystalline crystal particles, and the compressibility is poor, so that the requirements of conventional powder direct compression or dry granulation cannot be met. The direct powder tabletting process is suitable for medicines which are easy to discolor and decompose when exposed to moisture and heat, and has the most remarkable advantages that the equipment and operation cost is reduced, and material particles for direct powder tabletting have good flowability, compressibility and certain fineness or crystal form, otherwise, the phenomena of blanking, unqualified product properties and the like are easy to occur in the production process. Therefore, the difficulty of preparing the pregabalin orally disintegrating tablet preparation is to improve the compressibility of the material.
The pregabalin is a polycrystalline medicine, and comprises an anhydrous type, a semi-water type, crystal forms I-IV and an alpha type. The particular crystalline combination of polymorphic drugs has important effects on the physical properties of the product, such as storage, stability, compressibility, bulk density (which has an important impact on formulation and product manufacture) and dissolution (which has an important impact on determining bioavailability). On the other hand, a characteristic that a crystal spontaneously grows under a certain external condition tends to form a certain morphology is called crystal habit. The habit of crystallization is a short term for its crystal habit and is also called crystal habit, habit of crystallization, habit of crystal and habit of crystal. The classification of crystal habit is usually descriptive, not very strict, and it is difficult to find the definite number of classes and classification criteria. Common crystal habit classifications can be classified into lamellar, dendritic, knife-edge, needle, lenticular, sheet, depending on the crystal appearance; the method is divided into the following components according to the included angles between crystal faces: prisms, pyramids, plates; the method is divided into the following parts according to polyhedrons: cubic, octahedral, dodecahedral; the method is divided into the following according to the aggregation state of single crystals: fibrous, grape-like, radial, block-like; multiple crystal habits may also exist for a single crystal form of the same material. The physical properties of the crystal form and crystal habit of the drug are very important in the processing of the drug, and may affect the compressibility, flowability and the like of the intermediate product.
CN00812588 provides a process for preparing an immediate release pharmaceutical taste-masked granule by granulating a mixed powder of active substance, granule disintegrant, osmotic agent and sweetener using a binder, followed by coating with a coating agent to mask the taste. 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) in 5min, the rapid release cannot be realized, the bioavailability is low, and the coated tablet can be swallowed only and cannot be chewed, so the actual taking convenience is not high.
CN103271888 mentions that pregabalin bulk drug has poor compressibility, and provides a prescription which comprises pregabalin drug (10% -50%), disintegrant crospovidone (5% -30%), microcrystalline cellulose (20% -80%), and corrective, glidant and lubricant in balance; the preparation process comprises the following steps: mixing pregabalin, correctant, microcrystalline cellulose and disintegrant in a wet granulating machine, adding appropriate amount of water, granulating, drying, sieving, mixing the sieved granules with the rest adjuvants, and pressing into tablet with desired hardness. The pregabalin powder has poor compressibility, and the pregabalin orally disintegrating tablet developed by the invention overcomes the problem of poor compressibility of pregabalin. According to the invention, multiple tests show that the compressibility of the material can be improved through the granulating process, but the product pressed by the granulated material has obvious taste problem, the taste is gravel and the disintegration is slow; the finished product prepared by the powder direct-pressing process is melted in the mouth and has soft and glutinous mouthfeel. Therefore, to preserve the soft, waxy mouth feel of orally disintegrating tablets of pregabalin, the product mouth feel 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 energy consumption of the wet granulation process is high, the time consumption is long, and unnecessary stability risks are caused by the damp and hot conditions in the processing process.
CN111096953 provides a pregabalin orally disintegrating tablet which adopts silicified microcrystalline cellulose and can be directly tableted and a preparation method thereof. It mixes pregabalin and silicified microcrystalline cellulose, then mixes them with other auxiliary materials, then makes them undergo the process of powder direct compression. The prescription comprises pregabalin medicine (10-30%), disintegrant crospovidone (5-20%), filler silicified microcrystalline cellulose, spray-dried mannitol 200SD (10-80%), lubricant (0.5-2%) and corrective (1-3%). The method can improve the compressibility and fluidity of the material, so that the prepared orally disintegrating tablet has excellent stability. However, silicified microcrystalline cellulose is an expensive auxiliary material, the price of the silicified microcrystalline cellulose is 3 to 4 times of that of common microcrystalline cellulose, the dosage proportion of the prescription of the microcrystalline cellulose is 20 to 40 percent, and the increase of the cost is not beneficial to the market sale of products.
Generally, the compressibility of the particles in the process of preparing the pregabalin orally disintegrating tablet can be improved by adding auxiliary materials with better compressibility or reducing the proportion of pregabalin in the prescription, but the problems of tablet weight increase and size increase are caused, and the quantity of tablets produced in a single batch is reduced. The way of adding the binder affects the disintegration behavior of the product and prolongs the disintegration time of the product. The compressibility of the granules can be effectively improved by adopting a wet granulation mode, but the processing cost, the time cost and the like in the preparation process can be increased by adopting the process, and meanwhile, the risk of increasing the impurity content of the product can be increased by contacting with a damp heat factor. At present, most methods for improving the compressibility of granules in the process of preparing the pregabalin orally disintegrating tablet are to add auxiliary materials with better compressibility or carry out wet granulation, and the methods can increase the cost of products and influence the disintegration time limit condition of the products and the like
Disclosure of Invention
The purpose of the invention is as follows: aiming at the defects of the prior art, the invention provides the pregabalin composition suitable for powder tabletting, the compressibility of the material can be obviously improved by selecting the raw material medicines with specific crystal habit and particle size range and further compounding the raw material medicines with a filling agent, a lubricating agent and a disintegrating agent, and the pregabalin orally disintegrating tablet with excellent quality can be prepared by a simple mixed tabletting process.
In order to solve the technical problem, the invention discloses a pregabalin composition suitable for powder tabletting, wherein the pregabalin as an active component is pregabalin with square crystal habit, the particle size range is D90: 350-600 mu m, and the using amount accounts for 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 are percentages of the total mass of the prescription.
Wherein the filler is 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, methyl cellulose, hydroxypropyl starch, etc.; preferably, the filler is at least one of microcrystalline cellulose, dibasic calcium 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 one or more of superfine silica gel powder, talcum powder and magnesium stearate.
The lubricant is at least one of sodium stearyl fumarate, magnesium stearate, aerosil and talcum powder.
The flavoring agent is one or more of cyclamate, acesulfame potassium (acesulfame K, A-K sugar), aspartame, neotame, sucralose, sucrose, sorbitol, mannitol, and glucose; the essence is natural essence or artificial essence, preferably at least one of natural essence or artificial essence such as milk essence, grape essence, strawberry essence, vanillin, apple essence, orange essence, banana essence, orange oil, etc.
The composition further 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 gel 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) carrying out size stabilization on each raw material medicine by using a gate type size stabilization machine, carrying out size stabilization on each raw material medicine by using the gate type size stabilization machine, and after size stabilization, enabling the pregabalin to be the pregabalin with square crystal habit, wherein the particle 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 granules;
(3) and pressing the mixed granules by a tablet machine to obtain a plain tablet with the hardness of 4-6 kg.
Preferably, the mesh opening of the granulating machine is 0.8mm, and the granulating rotating speed is 300-700 rpm. The tablet prepared by the invention can be used for preparing an immediate release preparation for treating epilepsy and neuropathic pain.
Has the advantages that: compared with the prior art, the invention has the following advantages:
(1) through a large number of experiments and researches of the inventor, the invention obtains that: the pregabalin orally disintegrating tablet with excellent quality can be prepared by compounding the pregabalin bulk drug with the particle size range D90 of 350-600 mu m and square crystal habit, a filler, a lubricant and a disintegrant, and can remarkably improve the compressibility of the material. The quick release preparation can realize the quick release of the active ingredient pregabalin, so that the effective blood concentration can be quickly reached after oral administration; compared with the traditional capsule preparation, the quick-release preparation prepared by the invention has the advantages of quick response, quick absorption, stable effect, cool and slightly sweet taste, instant melting in the mouth, soft and glutinous taste, no intolerable bitter taste and capability of improving the compliance of patients.
(2) According to the preparation method, the pregabalin bulk drug is processed by adopting a gate type granulator to obtain the pregabalin bulk drug with specific crystal habit and a certain particle size range, and then the pregabalin bulk drug is mixed with various conventional auxiliary materials to prepare material particles with excellent compressibility by a relatively simple process, so that the material particles are used for preparing the pregabalin orally disintegrating tablets. The process has the advantages of simple operation, mature control standard, low cost, high industrialization degree and the like;
(3) the stability research experiment on the reference preparation shows that the change of quality indexes of the product in the stability investigation process, such as appearance, related substances, dissolution, hardness and the like, can be influenced due to the lower melting point of the lipid auxiliary material, and the use of the auxiliary material with higher price can also increase the product cost. The invention achieves the purposes of reducing the product cost and preparing the stable pregabalin quick-release preparation by simplifying the types of auxiliary materials and controlling the particle size and crystal habit of the pregabalin raw material medicine.
Drawings
The foregoing and/or other advantages of the invention will become further apparent from the following detailed description of the invention when taken in conjunction with the accompanying drawings.
FIG. 1 is a microscope picture of the raw material drug used in product 1;
FIG. 2 is a microscope photograph of the drug substance used in product 2;
FIG. 3 is a graph showing the particle size distribution of the raw material drug used in product 1;
FIG. 4 is a graph showing the particle size distribution of the raw material drug used in product 2;
FIG. 5 is a microscope photograph of the drug substance used in product 3;
FIG. 6 is a microscope photograph of the drug substance used in product 4;
FIG. 7 is a microscope photograph of the drug substance used in product 5;
FIG. 8 is a microscope photograph of the drug substance used in product 6;
fig. 9 is a microscope picture of the drug substance used in product 7.
Figure 10 is a photograph of dissolution profiles of product 1 and product 2 and a reference formulation.
Detailed Description
In order to better understand the present invention, the present invention and its advantages and advantageous effects will be described below by examples of the present invention and experimental data.
In the following examples, the product testing method was as follows:
the method for measuring and sampling the particle size of the raw material medicine comprises the following steps:
in a material bag filled with the whole-grain pregabalin bulk drug, 5g of the sample is respectively sampled from the upper, middle and lower 6 different positions, a sample is synthesized after sampling, 30g of the sample is sampled in total, and the sample is sent for detection of the particle size distribution.
The method for measuring the particle size of the raw material medicine comprises the following steps:
the method for measuring the particle size of the raw material medicine comprises the following steps: weighing 0.3g of dispersant span-85 in a 250ml beaker, adding 120ml of accurately measured n-heptane to obtain span-85 n-heptane solution with a certain proportion, placing the solution in a trace disperser, stirring the solution until the background is stable, measuring a 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 trace wet sampling window of a laser particle analyzer, operating a corresponding determination method file according to related parameter items, and taking the arithmetic average of the determination results for 3 times to obtain the particle size data of the raw material drug.
Analyzing the particle size data of the raw material medicines:
the meaning of particle size distribution is that the percentage of particles with different particle sizes in the powder sample in the total volume (or number, etc.) of the particles is measured by a specific instrument and method. D10: the cumulative (percentage of all preceding and following particle sizes added to itself) of a sample corresponds to the particle size at which the particle size distribution reaches 10%. Its physical meaning is that the particles have a size less than (or greater than) 10% of their size. D90: the cumulative particle size distribution of a sample reaches 90% of the corresponding particle size. Its physical meaning is that the particles having a size smaller (or larger) than it account for 90%. D50: the cumulative percent particle size distribution for a sample at 50% corresponds to the particle size. Its physical meaning is that the particle size is greater than 50% of its particles and less than 50% of its particles, D50 also being referred to as the median or median particle size. It does not mean the average particle size of the powder, and means that there are additional parameters to the average particle size of the powder, such as D (4,3), D (3, 2), and so forth. Both D (4,3) and D (3, 2) are volume-based average particle diameters. Wherein D (4,3) are all referred to as "mass moment volume average particle diameter" for short as volume average diameter. The calculation method is that the grain diameter values at two ends of each grain diameter interval are averaged, then the product is multiplied by the corresponding grain size distribution percentage of the interval, and the products are accumulated, namely D (4,3) ═ f 1. D1+ f 2. D2+ f 3. D3+ …. D (3, 2) are all referred to as "volume area average particle diameter", and are simply referred to as "area average particle diameter". The calculation method is to add the percentages of each particle size interval by the average value of the corresponding particle size interval and then to find the reciprocal, i.e., D (3, 2) ÷ (f1 ÷ D1+ f2 ÷ D2+ f3 ÷ D3+ …). Wherein: di represents the average particle size of the ith particle size interval, and fi represents the ith. The relationship between D (3, 2) and D (4,3) can be understood as follows: for laser particle sizers, the more spherical particles are approximated, the more accurate the measurement results. Then, the closer the values of D (3, 2) and D (4,3) are, the more regular the shape of the sample particles is, the more concentrated the particle size distribution is. The larger the difference, the more irregular the shape of the sample particles and the broader the particle size distribution.
The observation method of the crystal habit microscope of the raw material medicine comprises the following steps:
the crystal habit appearance of the raw material medicine is observed and measured by a microscope. Taking 0.01g of the pregabalin bulk drug on a glass slide, and dripping 1 drop of liquid paraffin for dispersion. The parameters of an ocular lens of the microscope are 10 times, the parameters of an objective lens are 5 times, and a picture with uniformly dispersed particles and sufficient illumination is observed and taken.
Fluidity, tablet friability, and maximum tablet hardness measurement methods:
100g of the total mixture was taken and the flowability of the material was measured using an FT-104B angle of repose tester. About 6.5g of the finished product was taken and tablet friability was measured using a CJY-300D type tablet friability tester. The hardness of the finished tablets was measured using a YPD-200C tablet hardness tester.
Example 1
the preparation process flow of the product 1 is as follows:
carrying out door type granulating machine granulation on pregabalin (D90 is 900 mu m, crystal habit is in a shape of long needle and square), sieving with a 0.8mm granulating sieve at a granulating speed of 700rpm, and finishing pregabalin D90 after granulation is 500 mu m, crystal habit is in a shape of square;
secondly, mixing microcrystalline cellulose, the sized pregabalin, mannitol, sucralose, saccharin sodium, polyvinylpolypyrrolidone SH-SL10 and mint essence by using a pyramid mixing barrel according to the dosage in the formula table of the product 1, wherein the mixing speed is 10rpm, and the mixing time is 20 min;
thirdly, screening the mixed granules obtained in the previous step by a 20-mesh vibrating screen, adding magnesium stearate into the screened granules, and mixing by using a square cone mixing barrel, wherein the mixing speed is 10rpm, and the mixing time is 20 min;
and fourthly, directly tabletting the powder by using the mixed particles obtained in the previous step.
mixing pregabalin (D90 is 900 microns, crystal habit is long needle-shaped and square), microcrystalline cellulose, mannitol, sucralose, saccharin sodium, cross-linked povidone SH-SL10 and mint essence by using a pyramid mixing barrel according to the dosage in the formula table of the product 2, wherein the mixing speed is 10rpm, and the mixing time is 20 min;
secondly, screening the mixed granules obtained in the previous step by a 20-mesh vibrating screen, adding magnesium stearate into the screened granules, and mixing by using a square cone mixing barrel, wherein the mixing speed is 10rpm, and the mixing time is 20 min;
and thirdly, directly tabletting the powder by using the mixed particles obtained in the previous step.
Microscope pictures of the raw material medicines used in the product 1 and the product 2 are respectively shown in figure 1 and figure 2, and the particle size distribution of the raw material medicines used in the product 1 and the product 2 is respectively shown in figure 3 and figure 4.
The properties of the raw material medicine and the tablet
Results and conclusions of the experiment
The D90 of the bulk drug of the product 1 after being granulated by the gate granulator is 500 μm, and the difference between D (4,3) and D (3, 2) is 74 μm. The D90 of the bulk drug of the product 2 is 900 μm, and the difference between D (4,3) and D (3, 2) is 575 μm. Compared with the product 2, the product 1 has small difference between the D (3, 2) and D (4,3) of the raw material medicines, which shows that the shape of the raw material medicine particles of the product 1 is more regular and the particle size distribution is centralized, and then the crystal habit is the cubic crystal according to the microscope picture. The difference between D (3, 2) and D (4,3) of the raw material medicine of the product 2 is large, which indicates that the raw material medicine of the product 2 has irregular particle shape and wide particle size distribution, and the crystal habit is uneven mixed crystal of square crystal and long needle crystal according to the microscope picture.
The tablet result shows that the product 1 with the D90 of 500 mu m is mainly in the form of the cristobalite, and has better material flowability than the product 2 with the bulk drug with the crystal habit mainly in the form of the long needle crystal and the cristobalite mixed crystal, and the pressed tablet has lower friability and higher highest compressible hardness. Therefore, the pregabalin bulk drug with the crystal habit mainly being the cubic crystal can effectively improve the flowability and the compressibility of the material and prepare the pregabalin orally disintegrating tablet with excellent properties.
Figure 10 is a dissolution profile for product 1 and product 2 and the 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, and the preparation steps are as follows: measuring 5.4ml of hydrochloric acid, diluting with water to 1000ml, and shaking up to obtain the final product.
Control solution: taking about 16mg of pregabalin control, precisely weighing, placing in a 100mL volumetric flask, adding a dissolution medium to dissolve, quantitatively diluting to a scale, and shaking up (the concentration is about 160 mug/mL). Two portions were prepared in parallel.
Preparing a mobile phase:
(1)0.04M diammonium hydrogen phosphate (pH6.5)
Accurately weighing 5.28g of diammonium hydrogen phosphate and ultrapure water, fixing the volume to 1000ml, adjusting the pH value to 6.5 +/-0.05 by using phosphoric acid, and performing suction filtration.
(2) Mobile phase: 0.04M diammonium hydrogen phosphate (ph 6.5): acetonitrile 90:10
Dissolution conditions:
dissolution medium: 0.06M hydrochloric acid
A dissolution device: paddle method
Rotating speed: 50rpm
Dissolution medium temperature: 37 +/-0.5 DEG C
Sampling volume and fluid infusion volume: 3.5ml of sample is taken, 2ml of waste liquid is dripped and no liquid is replenished.
Volume of dissolution medium: 900 ml.
A sample casting method comprises the following steps: and (4) randomly feeding samples.
Sample solution treatment: the mixture was filtered through a 0.45 μm water filtration head (Jinteng, polyethersulfone, 25mm), and 2ml of the initial filtrate was discarded, and the subsequent filtrate was used as a sample solution.
Sampling time points are as follows: 5. 10, 15 (min).
Detection conditions of a high performance liquid chromatograph:
a chromatographic column: GL Sciences Inertsil ODS-3V.
The oral disintegrating tablet of pregabalin was selected, and the pregabalin was first marketed in Japan in 2017, 02/17, with an english trade name of LYRICA (lereca), a japanese trade name of リリカ OD ingot, and a certificate holder of Pfizer Japan Inc (ファイザー co., ltd.), and the reference preparation was labeled EA 6596. As can be seen from the results, the dissolution curve of the product of the invention is similar to that of the reference preparation, and the in vitro results show that the product of the invention has the same quick effect and quick absorption as the reference preparation to a certain extent.
Example 2
Product 3 prescription table:
product 3 preparation process flow:
carrying out gate type granulating machine granulation on pregabalin (D90 is 900 mu m, crystal habit is in a shape of long needle and square), sieving with a 0.8mm granulating sieve, reducing the granulating speed from 700rpm to 300rpm of the lowest rotation speed of equipment, and obtaining pregabalin D90 with the particle habit of being in a shape of square after granulation, wherein the particle size of the pregabalin is 550 mu m;
secondly, mixing microcrystalline cellulose, the sized pregabalin, mannitol, sucralose, saccharin sodium, crospovidone SH-SL10 and mint essence by using a pyramid mixing barrel according to the dosage in the formula table of the product 3, wherein the mixing speed is 10rpm, and the mixing time is 20 min;
thirdly, screening the mixed granules obtained in the previous step by a 20-mesh vibrating screen, adding magnesium stearate into the screened granules, and mixing by using a square cone mixing barrel, wherein the mixing speed is 10rpm, and the mixing time is 20 min;
and fourthly, directly tabletting the powder by using the mixed particles obtained in the previous step.
The microscope picture of the raw material drug used in the product 3 is shown in fig. 5.
The properties of the raw material medicine and the tablet
Results and conclusions of the experiment
The rotating speed of the gate type granulator is reduced from 700rpm to 300rpm, and compared with the crude drug obtained at the granulating rotating speed of 700rpm, the difference values of D90, D (4,3) and D (3, 2) of the crude drug obtained at the granulating rotating speed of 300rpm have no obvious change. The tablet results show that compared with the product 1 of the raw material medicine obtained at the whole grain rotating speed of 700rpm, the material flowability, the friability of the pressed tablet and the highest pressable hardness of the product 3 of the raw material medicine obtained at the whole grain rotating speed of 300rpm have no obvious difference. Therefore, 700rpm with higher production efficiency is used as the granulating speed parameter of the gate-type granulator in the subsequent process production, and the operation is simple and easy to control.
Example 3
the preparation process flow of the product 4 is as follows:
carrying out size stabilization on the pregabalin (the D90 is 900 mu m, the crystal habit is in a long needle shape and a square shape) by a gate type size stabilization machine, changing a 0.8mm size stabilization screen into a 0.9mm screen, wherein the size stabilization speed is 700rpm, the pregabalin D90 is 700 mu m after size stabilization, and the crystal habit is in a long needle shape and a square shape.
Mixing microcrystalline cellulose, the sized pregabalin, mannitol, sucralose, saccharin sodium, crospovidone SH-SL10 and mint essence by using a pyramid mixing barrel according to the dosage in the formula table of the product 4, wherein the mixing speed is 10rpm, and the mixing time is 20 min;
thirdly, screening the mixed granules obtained in the previous step by a 20-mesh vibrating screen, adding magnesium stearate into the screened granules, and mixing by using a square cone mixing barrel, wherein the mixing speed is 10rpm, and the mixing time is 20 min;
and fourthly, directly tabletting the powder by using the mixed particles obtained in the previous step.
The microscope picture of the raw material drug used in the product 4 is shown in fig. 6.
The properties of the raw material medicine and the tablet
Results and conclusions of the experiment
The door type granulator is replaced by a 0.9mm screen when the screen is 0.8mm, and compared with the bulk drug obtained by 0.8mm screen when the screen is 0.9mm, the differences of D90, D (4,3) and D (3, 2) of the bulk drug obtained by 0.9mm screen when the screen is 0.8mm screen when the screen is 0 mm screen when the screen is whole are obviously increased. The combination of the raw material medicine microscope pictures shows that the pregabalin raw material medicine obtained by granulating through the 0.9mm screen is a long needle-shaped crystal and a square crystal mixed crystal, which is not as round as the raw material medicine obtained by granulating through the 0.8mm screen, and the whole grain size is larger, and D90 is 700 mu m. The tablet results show that, compared with product 1 of the raw material obtained by granulating through a 0.8mm sieve, product 4 of the raw material obtained by granulating through a 0.9mm sieve has slower material flowability, higher friability of the pressed tablet, lower highest compressible hardness and slower disintegration time limit. Therefore, a 0.8mm screen is used as the screen parameter of the gate-type granulator in the subsequent process production, the operation is simple and easy to control, and the product quality can be ensured.
Example 4
Product 5 prescription table:
the preparation process flow of the product 5 is as follows:
carrying out door type granulating machine granulation on pregabalin (D90 is 900 mu m, crystal habit is in a shape of long needle and square), changing a 0.8mm granulating screen into a 0.7mm screen, wherein the granulating speed is 700rpm, the pregabalin D90 is 350 mu m after granulation, and the crystal habit is in a shape of square;
secondly, mixing microcrystalline cellulose, the sized pregabalin, mannitol, sucralose, saccharin sodium, crospovidone SH-SL10 and mint essence by using a pyramid mixing barrel according to the dosage in the formula table of the product 5, wherein the mixing speed is 10rpm, and the mixing time is 20 min;
thirdly, screening the mixed granules obtained in the previous step by a 20-mesh vibrating screen, adding magnesium stearate into the screened granules, and mixing by using a square cone mixing barrel, wherein the mixing speed is 10rpm, and the mixing time is 20 min;
and fourthly, directly tabletting the powder by using the mixed particles obtained in the previous step.
The microscopic picture of the bulk drug used in product 5 is shown in fig. 7.
The properties of the raw material medicine and the tablet
Results and conclusions of the experiment
The door type granulator is replaced by the 0.7mm sieve for the 0.8mm sieve, and compared with the bulk drug obtained by the 0.8mm sieve for granulation, the difference value between D (4,3) and D (3, 2) of the bulk drug obtained by the 0.7mm sieve for granulation is not obviously changed, but D90 is obviously reduced, and the whole particle size is obviously reduced. The combination of the raw material medicine microscope pictures shows that the pregabalin raw material medicine obtained by granulating through a 0.7mm screen is a square crystal which is round, but the whole grain diameter is smaller, and D90 is 350 mu m. The tablet result shows that compared with the product 1 of the raw material medicine obtained by granulating through a 0.8mm screen, the material flowability of the product 5 of the raw material medicine obtained by granulating through a 0.7mm screen is not obviously changed, the friability of the pressed tablet is slightly increased, the highest compressible hardness is slightly reduced, the disintegration time limit is obviously slowed, the raw material medicine is supposed to be more fine powder, and the raw material medicine is easy to adhere to a screen of a disintegration tester during disintegration and cannot pass through smoothly, so that the disintegration time limit is longer. Therefore, a 0.8mm screen is used as the screen parameter of the gate-type granulator in the subsequent process production, the operation is simple and easy to control, and the product quality can be ensured.
Example 5
the preparation process flow of the product 6 is as follows:
crushing pregabalin (D90 is 900 mu m, crystal habit is long needle shape and square shape) by a traditional Chinese medicine crusher for 4s, wherein the obtained crushed pregabalin D90 is 200 mu m, and the crystal habit is square shape;
mixing microcrystalline cellulose, crushed pregabalin, mannitol, sucralose, saccharin sodium, crospovidone SH-SL10 and mint essence by using a pyramid mixing barrel according to the dosage in the formula table of the product 6, wherein the mixing speed is 10rpm, and the mixing time is 20 min;
thirdly, screening the mixed granules obtained in the previous step by a 20-mesh vibrating screen, adding magnesium stearate into the screened granules, and mixing by using a square cone mixing barrel, wherein the mixing speed is 10rpm, and the mixing time is 20 min;
and fourthly, directly tabletting the powder by using the mixed particles obtained in the previous step.
Method for measuring and sampling particle size of raw material medicine
Respectively sampling 5g of the crushed pregabalin bulk drug from 6 different positions of the upper part, the middle part and the lower part of a material bag filled with the crushed pregabalin bulk drug, synthesizing a sample after sampling, sampling 30g in total, and inspecting and detecting the particle size distribution.
The microscopic picture of the bulk drug used in product 6 is shown in fig. 8.
The properties of the raw material medicine and the tablet
Results and conclusions of the experiment
The whole grain procedure of the gate type granulator is changed into the crushing of the traditional Chinese medicine crusher, compared with the whole grain of the raw material medicine obtained by a screen with 0.8mm, the raw material medicine obtained by crushing the raw material medicine for 4s by the traditional Chinese medicine crusher has smaller difference between D (4,3) and D (3, 2), D90 is obviously changed to be smaller, and the whole grain diameter is obviously reduced. The combination of the raw material medicine microscope pictures shows that the pregabalin raw material medicine obtained by crushing with the traditional Chinese medicine crusher is a square crystal which is round, but the whole grain diameter is smaller, and D90 is 200 mu m. Tablet results show that compared with the product 1 of the raw material medicine obtained by granulating through a 0.8mm screen, the material flowability of the product 6 of the raw material medicine obtained by crushing for 4s through the traditional Chinese medicine crusher is slightly reduced, the friability of the pressed tablet is obviously increased, the highest compressible hardness is obviously reduced, and the disintegration time limit is obviously slower, so that the supposedly that the raw material medicine has more fine powder, is easy to adhere to the screen of a disintegration tester during disintegration and cannot pass through smoothly, and the disintegration time limit is longer. Therefore, the traditional Chinese medicine crushing process is difficult to replace a gate-type whole grain process, the crushing effect of the traditional Chinese medicine crushing process is difficult to control, the control standard is difficult to determine, the pregabalin bulk drug with specific crystal habit and certain particle size range cannot be obtained, and the pregabalin orally disintegrating tablets with qualified quality cannot be prepared.
Example 6
Product 7 prescription table:
the preparation process flow of the product 7 is as follows:
crushing pregabalin (D90 is 900 mu m, crystal habit is long needle shape and square shape) by a universal crusher, wherein the crushing screen is 0.8mm, the crushing rotating speed is 1500rpm which is the lowest rotating speed of the equipment, and the crushed pregabalin D90 is 250 mu m, and the crystal habit is square shape;
mixing microcrystalline cellulose, crushed pregabalin, mannitol, sucralose, saccharin sodium, crospovidone SH-SL10 and mint essence by using a pyramid mixing barrel according to the dosage in the formula table of the product 7, wherein the mixing speed is 10rpm, and the mixing time is 20 min;
thirdly, screening the mixed granules obtained in the last step by a 20-mesh vibrating screen, adding magnesium stearate into the screened granules, and mixing by using a square cone mixing barrel, wherein the mixing speed is 10rpm, and the mixing time is 20 min;
fourthly, the mixed particles obtained in the previous step are used for directly tabletting the powder.
Method for measuring and sampling particle size of raw material medicine
Respectively sampling 5g of the universal crushed pregabalin bulk drug from 6 different positions of the upper part, the middle part and the lower part of a material bag, synthesizing a sample after sampling, sampling 30g in total, and inspecting and detecting the particle size distribution.
The microscope picture of the bulk drug used for product 7 is shown in fig. 9.
The properties of the raw material medicine and the tablet
Results and conclusions of the experiment
The whole grain procedure of the gate-type granulator is changed into the crushing of a universal crusher, compared with the raw material medicine obtained by whole grain of the gate-type granulator with a screen of 0.8mm, the raw material medicine obtained by crushing of the universal crusher has smaller difference values of D (4,3) and D (3, 2), the D90 is obviously changed to be smaller, and the whole grain size is obviously reduced. The combination of the raw material medicine microscope pictures shows that the pregabalin raw material medicine obtained by crushing by the universal crusher is a square crystal which is round, but the whole grain diameter is smaller, and D90 is 250 mu m. The tablet results show that compared with the product 1 of the raw material drug obtained by granulating through a 0.8mm screen, the product 7 of the raw material drug obtained by crushing through the universal crusher has slightly reduced material flowability, slightly increased friability of the pressed tablet, slightly reduced highest compressible hardness and obviously slower disintegration time limit. Therefore, the universal crushing process is difficult to replace a portal size stabilization 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 certain particle size range cannot be obtained, and the pregabalin orally disintegrating tablets with qualified quality cannot be prepared.
Example 7
the preparation process flow of the product 8 is as follows:
dissolving mannitol in water according to a formula table of a product 8, and uniformly stirring to prepare a mannitol solution;
mixing microcrystalline cellulose, pregabalin, sucralose, saccharin sodium, crospovidone SH-SL10 and mint essence in a high-shear granulation pot, wherein the shearing speed is 500rpm, the stirring speed is 200rpm, and the mixing time is 10 min;
thirdly, spraying the mannitol solution into a high-shear granulation pot for granulation at the spraying speed of 15g/s and the atomizing pressure of 0.08MPa, wherein the shearing rotation speed is 1500rpm, the stirring rotation speed is 500rpm, and the granulation time is 3 min;
fourthly, the prepared particles are subjected to 8-8 mm wet granulation and then are put into a fluidized bed, the drying temperature is 45 ℃, and the fluidizing air speed is 60m3Drying for h, and performing gate-type size stabilization on the obtained dried particles by using a 0.8mm screen, wherein the rotation speed of size stabilization is 700 rpm;
adding magnesium stearate into the granules after finishing and mixing by using a square cone mixing barrel, wherein the mixing speed is 10rpm, and the mixing time is 20 min;
and sixthly, tabletting by using the mixed granules obtained in the previous step.
Tablet Properties
Evaluation of tablet mouthfeel
Results and conclusions of the experiment
The whole process of directly tabletting powder is changed into high-shear granulation tabletting, and the tablet result shows that compared with the pregabalin orally disintegrating tablet product 1 obtained by directly tabletting powder, the material flowability of the pregabalin orally disintegrating tablet product 8 obtained by high-shear granulation tabletting is not greatly changed, the friability of the pressed tablet is not greatly changed, the highest compressible hardness is slightly reduced, and the disintegration time limit is obviously slower, and supposedly, the raw material medicine particles are wrapped and covered after high-shear granulation, are not easily dissolved and dispersed during disintegration, so that the material particles are adhered to a screen of a disintegration instrument and cannot pass smoothly, and the disintegration time limit is longer. In the taste evaluation results of the tablets of 4 evaluators, the taste caused by products of different processes is not obviously different, but the taste evaluation of 4 evaluators on the product 8 shows that the product has poor taste and feelings of fine particles and the like, and overall, the taste of the product 1 prepared by directly tabletting powder is better. Therefore, the high-shear granulation tabletting process is not suitable for preparing the pregabalin orally disintegrating tablets, the high-shear granulation tabletting process is complicated, the production efficiency is low, the control standard is difficult to determine, and the pregabalin orally disintegrating tablets with qualified quality are not easy to prepare.
Example 8
Product 9 prescription table:
the preparation process flow of the product 9 is as follows:
dissolving mannitol in water according to a prescription table of a product 9, and uniformly stirring to prepare a mannitol solution;
② the pregabalin (D90 is 900 μm, crystal habit is long needle shape and square shape) is carried out the granulation by a gate type granulator, a 0.8mm granulation screen is adopted, and the granulation speed is 700 rpm.
Mixing microcrystalline cellulose, the sized pregabalin, sucralose, sodium saccharin, crospovidone SH-SL10 and mint essence in a high-shear granulation pot, wherein the shearing speed is 500rpm, the stirring speed is 200rpm, and the mixing time is 10 min;
fourthly, spraying the mannitol solution into a high-shear granulation pot for granulation at the spraying speed of 15g/s and the atomizing pressure of 0.08MPa, wherein the shearing rotation speed is 1500rpm, the stirring rotation speed is 500rpm, and the granulation time is 3 min;
fifthly, carrying out 8-8 mm wet granulation on the prepared particles, and then putting the particles in a fluidized bed, wherein the drying temperature is 45 ℃, and the fluidizing air speed is 60m3Drying for h, and performing gate-type size stabilization on the obtained dried particles by using a 0.8mm screen, wherein the rotation speed of size stabilization is 700 rpm;
sixthly, magnesium stearate is added into the granules after finishing the granules and mixed by using a pyramid mixing barrel, the mixing speed is 10rpm, and the mixing time is 20 min;
seventhly, tabletting by using the mixed particles obtained in the previous step.
Tablet Properties
Results and conclusions of the experiment
The whole process of directly tabletting powder is changed into the process of carrying out gate-type whole granulation on the raw material medicine and then carrying out high-shear granulation tabletting, and the tablet result shows that compared with the pregabalin orally disintegrating tablet product 1 obtained by directly tabletting powder, the material flowability of the pregabalin orally disintegrating tablet product 9 obtained by carrying out gate-type whole granulation on the raw material medicine and then carrying out high-shear granulation tabletting is not changed greatly, the friability of the pressed tablet is not changed greatly, the highest compressible hardness is not changed greatly, but the disintegration time limit is still slow, and after the high-shear granulation, the raw material medicine particles are wrapped and covered by the gate-type whole granulation, and the raw material particles are still not dissolved and dispersed easily during disintegration, so that the material particles are adhered to a sieve of a disintegration instrument, cannot pass smoothly, and the disintegration time limit is longer. Therefore, the direct powder tabletting process is more suitable for preparing the pregabalin orally disintegrating tablets, the high-shear granulation tabletting process is complicated, the production efficiency is low, the control standard is difficult to determine, and the pregabalin orally disintegrating tablets with qualified quality are not easy to prepare.
Summary of the invention
At present, the particle size range of the common pregabalin bulk drug sold on the market is about 800-1100 microns, and the crystal habit is long acicular and square crystal mixed crystal. The pregabalin bulk drug has poor compressibility and flowability, and cannot be used for preparing pregabalin orally disintegrating tablets. The method has the advantages that the door type granulator is used for granulating, the granulating screen is 0.8mm, the granulating rotating speed is 700rpm, the pregabalin bulk drug with the particle size range of 350-600 mu m, the difference range of D (4,3) and D (3, 2) is smaller and 50-150 mu m and the crystal habit is square can be efficiently and easily prepared, the flowability and the compressibility of the pregabalin bulk drug which is commonly sold on the market at present can be effectively improved, and the purposes of simple production process operation, mature control standard, low cost, high industrialization degree and good quality of pregabalin orally disintegrating tablets are achieved. In conclusion, the invention provides another idea, compared with the common pregabalin bulk drug, the prepared total mixed material has obviously improved compressibility by preparing the pregabalin bulk drug with a certain particle size range and a specific crystal habit form, and no extra expensive auxiliary material is used in the process of preparing the total mixed material.
While the methods of the present invention have been described in terms of preferred embodiments, it will be apparent to those of ordinary skill in the art that variations and modifications of the methods and applications described herein, as well as other suitable variations and combinations, may be made to implement and use the techniques of the present invention within the context, spirit and scope of the invention. Those skilled in the art can modify the process parameters appropriately to achieve the desired results with reference to the disclosure herein. It is expressly intended that all such similar substitutes and modifications which would be obvious to those skilled in the art are deemed to be included within the invention.
Claims (10)
1. The pregabalin composition suitable for powder tabletting is characterized in that the pregabalin as an active component is pregabalin with square crystal habit, the particle size range is D90: 350-600 mu m, and the using amount accounts for 20-50% of the total weight of the prescription.
2. The pregabalin composition of claim 1, further comprising a filler, a disintegrant, a flavoring agent, a fragrance, and a lubricant.
3. The pregabalin composition according to claim 2, characterized in that the amount of the filler is 0.0-80.0%, the amount of the flavoring agent is 0.1-15.0%, the amount of the disintegrating agent is 1.0-20.0%, and the amount of the lubricant is 0.5-3.0%, wherein the percentages are percentages of the total mass of the prescription.
4. The pregabalin composition of claim 2, wherein the filler is any one or both of a cellulose derivative and a starch derivative.
5. The pregabalin composition of claim 2, wherein the disintegrant is at least one of croscarmellose sodium, crospovidone, low substituted hydroxypropyl cellulose, or sodium carboxymethyl starch.
6. The pregabalin composition of claim 2, wherein the lubricant is at least one of sodium stearyl fumarate, magnesium stearate, aerosil, and talc.
7. The pregabalin composition according to claim 2, wherein the flavoring agent is any one or more of cyclohexylsulfamate, acesulfame potassium, aspartame, aspartyl alanine amide, neotame, sucralose, sucrose, sorbitol, mannitol, and glucose; the essence is natural essence or artificially synthesized essence.
8. The pregabalin composition according to claim 2, further comprising a glidant, wherein the glidant is any one or more of aerosil, talc and magnesium stearate.
9. Use of a pregabalin composition according to any of the claims 1 to 8 for the preparation of pregabalin tablets.
10. A preparation method of a pregabalin tablet is characterized by comprising the following steps:
(1) carrying out size stabilization on each raw material medicine by using a gate type granulator, and after size stabilization, enabling the pregabalin to be the pregabalin with square crystal habit, wherein the particle 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 granules;
(3) and pressing the mixed granules by a tablet machine to obtain a plain tablet with the hardness of 4-6 kg.
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| CN202210155830.6A CN114469880B (en) | 2022-02-21 | 2022-02-21 | Pregabalin composition suitable for powder tabletting and application thereof |
| PCT/CN2023/074166 WO2023155682A1 (en) | 2022-02-21 | 2023-02-01 | Pregabalin composition suitable for powder tableting and use thereof |
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| WO2023155682A1 (en) * | 2022-02-21 | 2023-08-24 | 广州帝奇医药技术有限公司 | Pregabalin composition suitable for powder tableting and use thereof |
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| WO2017064192A1 (en) * | 2015-10-14 | 2017-04-20 | Laboratorios Lesvi, S.L. | Pregabalin compositions |
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| CN112121020A (en) * | 2019-06-24 | 2020-12-25 | 北京万全德众医药生物技术有限公司 | Preparation method of pregabalin orally disintegrating tablet |
| CN114469880B (en) * | 2022-02-21 | 2024-02-02 | 广州帝奇医药技术有限公司 | Pregabalin composition suitable for powder tabletting and application thereof |
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| WO2023155682A1 (en) * | 2022-02-21 | 2023-08-24 | 广州帝奇医药技术有限公司 | Pregabalin composition suitable for powder tableting and use thereof |
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