Pregabalin pharmaceutical composition and preparation method therefor

Abstract

The present invention relates to the technical field of pharmaceutic preparations, and provides a pregabalin pharmaceutical composition and a preparation method therefor. According to the present invention, by compounding sustained-release polymer materials having different viscosity grades for use, stable release performance can be obtained, slow release within 24 hours is realized, the requirement of once daily administration is satisfied, the release of the compound is smoother than that of LYRICA CR tablets, and the dissolution rate in 24 hours is also superior to that of the LYRICA CR tablets. The dissolution curves F2 of pregabalin sustained-release tablets of different sizes, which are prepared according to the present invention, in different media (0.06 M HCl, pH 4.5, pH 6.8) are all greater than 50, so that the requirements for waiving BE studies for different sizes are met.

Description

Pregabalin pharmaceutical composition and preparation method thereof

[0001] The present invention claims priority to the Chinese patent application filed with the Patent Office of China on June 12, 2023, with application number 202310687324.6 and invention name “A Pregabalin Pharmaceutical Composition and Its Preparation Method”, the entire contents of which are incorporated by reference into the application. Technical Field

[0002] The present invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a pregabalin pharmaceutical composition and a preparation method thereof. Background Art

[0003] Pregabalin, a γ-aminobutyric acid (GABA) analogue first developed by Warner-Lambert, is chemically known as (3S)-3-aminomethyl-5-methylhexanoic acid. Studies have shown that pregabalin binds to specific ligands of the α1δ subunit of voltage-dependent calcium channels in presynaptic neurons, thereby inhibiting calcium influx into nerve cells, reducing the release of excitatory amino acids and neurotransmitters, and suppressing neuronal hyperexcitation, resulting in analgesic, anti-epileptic, and anti-anxiety effects.

[0004] Pregabalin is a highly soluble and permeable Biopharmaceutics Classification System (BCS) Class I drug that reaches c 1.5 h after oral administration. max The relative bioavailability is more than 90% and is not affected by dose and food intake; the predictable linear kinetic characteristics show that c max The AUC and AUC are linearly related to the dose of single or multiple administrations; in addition, pregabalin does not bind to plasma proteins in the body and has almost no metabolism. In order to reduce the peak-to-valley effect of blood drug concentration, reduce the incidence of adverse drug reactions of pregabalin, and reduce the frequency of patient medication to improve compliance, Pfizer developed the pregabalin capsule LYRICA IR, which was launched in 2004. The recommended dose is 150-600 mg per day, administered in 2 or 3 times. Current clinical studies have shown that frequent use of pregabalin capsules can lead to large fluctuations in blood drug concentrations in the body, which in turn can cause patients to experience adverse reactions such as dizziness, headache, vomiting, and drowsiness. In addition, the treatment of diseases such as neuralgia and epilepsy requires long-term or even lifelong medication, so there is a strong market demand for developing pregabalin into a sustained-release preparation.

[0005] In the original LYRICA IR capsule formulation, pregabalin's short half-life limited its ability to maintain therapeutic effect, requiring multiple dosing every 8 hours. To overcome this limitation, Pfizer designed and developed LYRICA CR tablets, with a strength of 330 mg. The main ingredients include: Kollidon SR (polyvinyl acetate, povidone, sodium lauryl sulfate and silicon dioxide), crospin, polyethylene oxide, carbomer, magnesium stearate, polyvinyl alcohol, titanium dioxide, talc, polyethylene glycol, and colorants as inactive ingredients. NDA N209501 was approved in the United States on October 11, 2017. It is designed to release the drug over a longer period of time.

[0006] Patent (CN112957337A) provides a pregabalin pharmaceutical composition comprising pregabalin sustained-release micropellets with a particle size of 200-2500 μm, an excipient or a lubricant. By mass fraction, the pregabalin sustained-release micropellets contain 10%-95%, the excipient contains 10%-50%, and the lubricant contains 0.1%-5%. The active ingredient of the pregabalin sustained-release micropellets is pregabalin or a pharmaceutically acceptable salt thereof, and the amount of the active ingredient accounts for approximately 10%-70% of the mass of the pregabalin sustained-release micropellets. Micropellets have the advantages of increased bioavailability, unaffected by food, and stable release. Through the steps of dissolution, mixing, fluidized bed drying, and tableting, tablets, capsules, and pills are prepared. The resulting pregabalin extended-release composition has the characteristics of uniform content, stable drug release, high bioavailability, and good stability. This patent first prepares the micropellets, which makes granulation difficult during mass production.

[0007] The patent (CN114762682A) provides a pregabalin sustained-release tablet containing pregabalin or its salt or hydrate as an active ingredient, a gel skeleton material, and a swelling material; the gel skeleton material contains alginate and calcium salt, and the swelling material contains polyoxyethylene N60K. By improving the release rate and release rate of the formulation in the dissolution medium of pH 6.8 phosphate solution and reducing the difference with the dissolution medium of 0.06 mol / L hydrochloric acid solution, the bioavailability of the drug after meals and on an empty stomach is improved.

[0008] Patent (WO2016062182A1) discloses a sustained-release formulation of pregabalin, which consists of a pharmaceutically active ingredient containing pregabalin or its salt or hydrate, a gel matrix material containing alginic acid, and a swelling material containing polyethylene oxide. In this sustained-release formulation, the release of pregabalin is controlled by the gel matrix material and the swelling material, and the release time and gastric retention characteristics are controlled by changing the amount of the gel matrix material and the swelling material. Therefore, by controlling the pregabalin release matrix with a limited absorption window, the sustained-release formulation can achieve once-daily administration.

[0009] Patent CN104906064A discloses a pregabalin gastric floating sustained-release tablet and its preparation method. The pregabalin gastric floating sustained-release formulation comprises the following ingredients by weight: 5-40% pregabalin, 10-40% skeleton material, 1-20% bulking agent, 10-40% bleaching agent, and 5-40% diluent. This novel oral formulation achieves delayed release of pregabalin and prolongs its retention time in the stomach and upper small intestine, improving bioavailability, achieving stable blood concentrations, and reducing the need for frequent dosing.

[0010] Patent (CN110585153A) discloses a pregabalin sustained-release composition and a preparation method thereof, which comprises: (a) an active ingredient, wherein the active ingredient comprises pregabalin or a pharmaceutically acceptable salt or hydrate thereof; (b) a matrix-forming agent; (c) a swelling agent; and (d) a gelling agent; wherein the swelling agent is selected from one or a combination of at least two of cross-linked carboxymethyl cellulose sodium, cross-linked carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, and polyethylene oxide. The provided pregabalin sustained-release composition can rapidly expand in volume upon contact with an aqueous medium, exceeding the diameter of the human stomach pylorus (13 mm), thereby prolonging gastric emptying time to increase the retention time of pregabalin in the stomach and improving the absorption of pregabalin in the small intestine and ascending colon. At the same time, the provided pregabalin sustained-release composition achieves a 24-hour slow release, enabling QD (once daily) dosing, reducing the number of medications and improving patient compliance.

[0011] It can be seen that in the prior art, a specific swelling agent is mainly used to regulate the swelling properties of pregabalin sustained-release tablets to increase their retention time in the stomach, thereby improving bioavailability, obtaining a stable blood drug concentration, and reducing the number of times taken. Since the pH of gastric juice before and after eating is not constant, and the swelling properties of the swelling material vary at different pH values, it is easy to cause instability in the performance of pregabalin sustained-release tablets. In addition, the use of a specific swelling agent limits industrial production. Therefore, it is necessary to provide a pregabalin pharmaceutical composition that can obtain a stable release performance by compounding sustained-release polymer materials of different viscosity grades, achieving slow release within 24 hours, meeting the requirement of once-daily dosing, and the prepared pregabalin sustained-release tablets have a dissolution curve F2 greater than 50 in different media (0.06M HCl, pH4.5, pH6.8), meeting the requirements of size BE exemption.

[0012] Summary of the Invention

[0013] The present invention addresses the problems of the prior art and provides a pregabalin pharmaceutical composition and preparation method thereof. By utilizing sustained-release polymer materials of varying viscosity grades, the present invention achieves a smooth release profile, enabling slow release over 24 hours, meeting the requirement for once-daily dosing. The release rate is smoother than that of LYRICA CR tablets, and the 24-hour dissolution rate is also superior to that of LYRICA CR tablets. The pregabalin sustained-release tablets of varying strengths prepared by the present invention exhibit dissolution curves F2 greater than 50 in various media (0.06M HCl, pH 4.5, and pH 6.8), meeting the requirements for bioavailability exemptions for both large and small sizes.

[0014] In order to achieve the above objectives, in a first aspect, the present invention provides a pregabalin pharmaceutical composition comprising the following raw materials by weight:

[0015] Wherein, the active ingredient is selected from pregabalin or a pharmaceutically acceptable salt, complex, solvate or polymorph thereof; the sustained-release polymer material is a mixture of high-viscosity hydroxypropyl methylcellulose and hydroxypropyl cellulose; and the hydroxypropyl cellulose is hydroxypropyl cellulose having a 1% aqueous solution viscosity of 1500-3000 mPa.s.

[0016] For water-soluble drugs, drug release is primarily through diffusion from the matrix gel layer; for poorly soluble drugs, gradual hydration and dissolution of the matrix is ​​the primary mechanism. Hydrophilic gel matrix tablets generally require the use of high-viscosity hydroxypropyl methylcellulose (HPMC). Polymer viscosity influences drug release from hydrophilic gel matrix tablets in two ways. First, high-viscosity HPMC has significant intrinsic water absorption and a relatively high hydration rate. For example, the hydration rate of HPMC is linearly correlated with the inverse of its viscosity. The polymer on the surface of the hydrophilic gel matrix tablet hydrates, forming a gel layer through which the drug must diffuse. Second, the gel layer formed by high-viscosity HPMC also has a high viscosity, effectively reducing the drug diffusion rate. By compounding different high-viscosity grades of HPMC, drug release and dissolution properties can be fine-tuned.

[0017] Hydroxypropyl cellulose can also be used to produce tablets with extended drug release. Hydroxypropyl methylcellulose has different grades based on its solution viscosity. The present invention selects hydroxypropyl cellulose with a 1% aqueous solution viscosity of 1500-3000 mPa.s and uses it in combination with high-viscosity grade HPMC to prepare a pregabalin pharmaceutical composition with ideal sustained-release properties.

[0018] In a preferred embodiment, the high viscosity hypromellose is a mixture of high viscosity hypromellose 1 and high viscosity hypromellose 2; the high viscosity hypromellose 1 is selected from E10M CR, K100M, K100M CR, and more preferably K100M CR; the high viscosity hypromellose 2 is selected from K4M, K4M CR, and more preferably K4M CR; the hydroxypropyl cellulose is selected from HF or HXF, and more preferably HXF; the mass ratio of the high viscosity hypromellose 1, high viscosity hypromellose 2 and hydroxypropyl cellulose is 22.07:(4-11):(10-15), and more preferably 22.07:(5-10):12.93.

[0019] In a preferred embodiment, the high viscosity hypromellose is a mixture of K100M and K4M.

[0020] In a preferred embodiment, the filler is selected from one or more of lactose, mannitol, and microcrystalline cellulose, more preferably microcrystalline cellulose, and more preferably microcrystalline cellulose PH 101, PH102, PH105, and KG802.

[0021] Microcrystalline cellulose is widely used as a filler in direct compression, wet granulation, and roller compaction. Although literature reports indicate that MCC may physically bind or adsorb the drug substance, no physical interaction was evident in dissolution studies of the formulation. Based on acceptable flowability and compression properties, microcrystalline cellulose is preferred as a filler.

[0022] In a preferred embodiment, the pharmaceutically acceptable salt of pregabalin is selected from pharmaceutically acceptable salts formed by pregabalin with an organic acid, an inorganic acid, an organic base or an inorganic base, more preferably one of the hydrochloride, hydrobromide, hydrogen sulfate, sodium salt, potassium salt and magnesium salt of pregabalin.

[0023] In a preferred embodiment, the lubricant is selected from micronized silica gel, hydrogenated vegetable oil, magnesium stearate, stearic acid, sodium stearyl fumarate or talc, more preferably magnesium stearate.

[0024] In a preferred embodiment, the coating material is selected from Opadry and coating premix 03F670000-CN.

[0025] In a second aspect, the present invention provides a method for preparing the above-mentioned pregabalin pharmaceutical composition, comprising the following steps:

[0026] 1) Tablet preparation:

[0027] a) Pretreatment: granulating the hydroxypropyl cellulose;

[0028] b) adding the pretreated hydroxypropyl cellulose obtained in step 1a), part of the filler, and the active ingredient into a wet granulator, and then adding the remaining amount of filler and hydroxypropyl methylcellulose into the wet granulator, mixing evenly, granulating, and drying;

[0029] c) mixing the wet granulated material with a lubricant in a mixer, and pressing the mixed material into tablets after uniform mixing to obtain tablet cores;

[0030] 2) Coating:

[0031] a) Preparation of coating solution: Add the coating material to the solvent and stir until completely dissolved to obtain a coating solution;

[0032] b) Coating: The core tablets obtained in step 1c) are coated with the coating solution prepared in step 2a), and after reaching the target weight gain, the tablets are aged and dried to obtain coated tablets containing a coating film.

[0033] In a preferred embodiment, the wetting agent in step 1c) is selected from isopropyl alcohol and / or purified water.

[0034] In a preferred embodiment, the solvent in step 2a) is selected from one or more of acetone, purified water, and anhydrous ethanol.

[0035] Compared with the prior art, the present invention has the following beneficial effects:

[0036] 1. The present invention uses a compound of sustained-release polymer materials of different viscosity grades to achieve a smooth release performance, achieving slow release within 24 hours, meeting the requirement of once-daily dosing. The release is smoother than that of LYRICA CR tablets, and the 24-hour dissolution rate is also better than that of LYRICA CR tablets.

[0037] 2. The dissolution curves F2 of the pregabalin sustained-release tablets of different specifications prepared by the present invention in different media (0.06 M HCl, pH 4.5, pH 6.8) are all greater than 50, meeting the requirements for BE exemption for both large and small specifications. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] FIG1 shows the dissolution curves of the reference preparation of Comparative Example 1 in various media at 50 rpm using the USP II method at 900 mL.

[0039] Figure 2 Dissolution curves of pregabalin sustained-release tablets of different strengths in 0.06M HCl medium.

[0040] Figure 3 Dissolution curves of pregabalin sustained-release tablets of different strengths in pH 4.5 medium.

[0041] Figure 4 Dissolution curves of pregabalin sustained-release tablets of different strengths in pH 6.8 medium. DETAILED DESCRIPTION

[0042] It is worth noting that the raw materials used in the present invention are all common commercially available products, and their sources are not specifically limited.

[0043] Examples 1-4

[0044] The formulation compositions of Examples 1-4 are shown in Table 1-2.

[0045] The preparation process includes the following steps:

[0046] 1) Tablet preparation:

[0047] a) Pretreatment: granulating hydroxypropyl cellulose HXF;

[0048] b) adding the pretreated hydroxypropyl cellulose HXF obtained in step 1a), 50% of the microcrystalline cellulose PH102, and pregabalin to a wet granulator, and then adding the remaining amount of microcrystalline cellulose PH102, hypromellose K100M CR, and hypromellose K4M CR to the wet granulator, mixing uniformly, spraying with a wetting agent of isopropyl alcohol for granulation, and drying;

[0049] c) adding magnesium stearate to the wet granulated material in a mixer, mixing the mixture evenly, and tableting to obtain tablet cores;

[0050] 2) Coating:

[0051] a) Preparation of coating solution: Add Opadry to 9 times the amount of purified water and stir until completely dissolved to obtain a coating solution;

[0052] b) Coating: The core tablets obtained in step 1c) are coated with the coating solution prepared in step 2a), and after reaching the target weight gain, the tablets are aged and dried to obtain coated tablets containing a coating film.

[0053] Comparative Example 1

[0054] LYRICA CR tablets (Lot No: DN5396), 330 mg, manufactured by Pfizer.

[0055] Comparative Example 2

[0056] The formula is shown in Table 2, and the preparation process is the same as that of Examples 1-4.

[0057] Comparative Example 3

[0058] The total amount of hypromellose K100M CR and hypromellose K4M CR is the same as that in Example 3, the ratio of the total amount of hypromellose to hydroxypropyl cellulose is still 27.07:12.93, the mass ratio of K100M CR to K4M CR is adjusted to 1:1, that is, K100M CR:K4M CR:HXF=13.535:13.535:12.93, and the rest is the same as in Example 3.

[0059] Comparative Example 4

[0060] The hydroxypropyl cellulose HXF was replaced by MXF, and the rest was the same as in Example 3.

[0061] Test Example: Determination of Release

[0062] All dissolution studies were performed using a USP-II apparatus at 50 rpm, media: 0.06 M HCl, pH 1.2, pH 4.5, pH 6.8, a dissolution volume of 900 mL, and a temperature of 37.5 ± 0.5 °C.

[0063] Table 1 Formula composition of Examples 1-4

[0064] Table 2 Formulations of Example 4 and Comparative Example 2

[0065] 1. The dissolution results of Examples 1-4 and Comparative Examples 1-4 in 0.06 M HCl medium are shown in Table 3. It can be seen that the release of Examples 1-4 and Comparative Examples 2-4 is smoother than that of Comparative Example 1 (reference reagent), while the 24-hour dissolution rate is comparable. In 0.06 M HCl medium, there is little difference between Examples 1-4 and Comparative Examples 2-4.

[0066] Table 3: Dissolution curve test results of pregabalin sustained-release tablets (0.06M HCl)

[0067] 2. The dissolution results of Examples 1-4 and Comparative Examples 1-4 in pH 1.2, pH 4.5, and pH 6.8 media are shown in Tables 4-6. As can be seen from Table 6, the dissolution degrees of the reference preparations of Comparative Example 2 and Comparative Example 1 in pH 1.2, pH 4.5, and pH 6.8 media are similar. As can be seen from Tables 4-5, Examples 1-4 have significantly better 24-hour dissolution rates in pH 4.5 and pH 6.8 media than the reference preparations of Comparative Example 1 and Comparative Examples 2-4.

[0068] Table 4 Dissolution curve test results of pregabalin sustained-release tablets (pH 4.5)

[0069] Table 5 Dissolution curve test results of pregabalin sustained-release tablets (pH 6.8)

[0070] Table 6 Pregabalin sustained-release tablet dissolution curve test results (Comparative Examples 1-2)

[0071] 3. Tables 7-9 and Figures 2-4 describe the dissolution results of different strengths of pregabalin sustained-release tablets (165 mg and 330 mg) in different media. It can be seen that the dissolution curve F2 of the pregabalin sustained-release tablets of Example 1 (strength: 165 mg) and the pregabalin sustained-release tablets of Example 2 (strength: 330 mg) in different media (0.06 M HCl, pH 4.5, pH 6.8) is greater than 50, meeting the requirements for biowaiver for both sizes.

[0072] Table 7 Dissolution curve test results of pregabalin sustained-release tablets of different specifications 0.06M HCl

[0073] Table 8: pH 4.5 dissolution curve test results of pregabalin sustained-release tablets of different specifications

[0074] Table 9: pH 6.8 dissolution curve test results of pregabalin sustained-release tablets of different specifications

[0075] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, rather than to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions of the technical solution of the present invention by ordinary technicians in this field do not deviate from the essence and scope of the technical solution of the present invention.

Claims

1. A pregabalin pharmaceutical composition, characterized in that In terms of weight percentage, it includes the following raw materials: Wherein, the active ingredient is selected from pregabalin or a pharmaceutically acceptable salt, complex, solvate or polymorph thereof; the sustained-release polymer material is a mixture of high-viscosity hydroxypropyl methylcellulose and hydroxypropyl cellulose; and the hydroxypropyl cellulose is hydroxypropyl cellulose having a 1% aqueous solution viscosity of 1500-3000 mPa.s.

2. The pregabalin pharmaceutical composition according to claim 1, wherein The high-viscosity hypromellose is a mixture of high-viscosity hypromellose 1 and high-viscosity hypromellose 2; the hypromellose 1 is selected from E10M CR, K100M, and K100M CR; the high-viscosity hypromellose 2 is selected from K4M and K4M CR; the hydroxypropyl cellulose is selected from HF or HXF; the mass ratio of the high-viscosity hypromellose 1, high-viscosity hypromellose 2, and hydroxypropyl cellulose is 22.07:(4-11):(10-15).

3. The pregabalin pharmaceutical composition according to claim 2, wherein The mass ratio of the high viscosity hypromellose 1, high viscosity hypromellose 2, and hydroxypropyl cellulose is 22.07:(5-10):12.

93.

4. The pregabalin pharmaceutical composition according to claim 2, wherein The high-viscosity hypromellose is a mixture of K100M CR and K4M CR, and the hydroxypropyl cellulose is HXF.

5. The pregabalin pharmaceutical composition according to claim 1, wherein The filler is selected from one or more of lactose, mannitol, and microcrystalline cellulose.

6. The pregabalin pharmaceutical composition according to claim 1, wherein The filler is microcrystalline cellulose, and the microcrystalline cellulose is selected from PH101, PH102, PH105, and KG802.

7. The pregabalin pharmaceutical composition according to claim 1, wherein The pharmaceutically acceptable salt of pregabalin is selected from pharmaceutically acceptable salts formed by pregabalin and an organic acid, an inorganic acid, an organic base or an inorganic base.

8. The pregabalin pharmaceutical composition according to claim 1, wherein The lubricant is selected from micro powder silica gel, hydrogenated vegetable oil, magnesium stearate, stearic acid, sodium stearyl fumarate or talc.

9. The pregabalin pharmaceutical composition according to claim 8, wherein The lubricant is magnesium stearate.

10. The pregabalin pharmaceutical composition according to claim 1, wherein The coating material is selected from Opadry and coating premix 03F670000-CN.

11. The method for preparing the pregabalin pharmaceutical composition according to any one of claims 1 to 10, wherein: The steps include: 1) Tablet preparation: a) Pretreatment: granulating the hydroxypropyl cellulose; b) adding the pretreated hydroxypropyl cellulose obtained in step 1a), part of the filler, and the active ingredient into a wet granulator, and then adding the remaining amount of filler and hydroxypropyl methylcellulose into the wet granulator, mixing evenly, granulating, and drying; c) mixing the wet granulated material with a lubricant in a mixer, and pressing the mixed material into tablets after uniform mixing to obtain tablet cores; 2) Coating: a) Preparation of coating solution: Add the coating material to the solvent and stir until completely dissolved to obtain a coating solution; b) Coating: The core tablets obtained in step 1c) are coated with the coating solution prepared in step 2a), and after reaching the target weight gain, the tablets are aged and dried to obtain coated tablets containing a coating film.

12. The preparation method according to claim 11, wherein The wetting agent in step 1c) is selected from isopropyl alcohol and / or purified water.

13. The preparation method according to claim 11, wherein The solvent in step 2a) is selected from one or more of acetone, purified water, and anhydrous ethanol.

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