Bidirectional positioning release sustained-release pharmaceutical composition and preparation method thereof

Abstract

The invention discloses a two-way positioning release sustained-release pharmaceutical composition and a preparation method thereof, the pharmaceutical composition is a double-layer tablet, and the double-layer tablet comprises an upper-layer tablet and a lower-layer tablet. The upper-layer tablet is a slow-release intragastric positioning release preparation part and contains 1 / 3 marked amount of active ingredients; the lower-layer tablet is a quick-release gastrointestinal tract release preparation part and contains 2 / 3 labeled amount of active ingredients. A new preparation technology and a new dosage form are adopted, the lower-layer tablet in the double-layer tablet can enable the medicine to be rapidly disintegrated in the stomach, the disintegrated medicine forms a particle dispersion, and the particle dispersion can be rapidly emptied by the stomach to enter the intestinal tract, so that the absorption of the medicine is promoted; the upper-layer tablet floats in the stomach after absorbing water, then the medicine is slowly dissolved out, the medicine dissolved out of the preparation can be metabolized into active metabolite OP-1118 in an acid environment in the stomach, then the active metabolite OP-1118 is absorbed through the gastrointestinal tract, and part of the medicine can be absorbed immediately after uniformly and slowly entering the intestinal tract, so that the bioavailability is improved.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of pharmaceutical preparation, more particularly to a bidirectional positioning release sustained-release pharmaceutical composition and a preparation method thereof. BACKGROUND

[0002] Fidaxomicin, also known as Fidaxomicin, is a new type of antibiotic, mainly used for the treatment of infection (CDI) caused by Clostridium difficile. Fidaxomicin is an 18-membered macrolide antibiotic produced by fermentation of the orange-encased Saccharopolyspora. Clinical trials have shown that fidaxomicin has better cure rate and recurrence rate than vancomycin, and the FDA approved its tablet in 2011. The listing of fidaxomicin provides an effective treatment option for this common and difficult infection.

[0003] Clostridium difficile is a bacterium that can cause severe infection in the intestine, especially after long-term use of other antibiotics. Clostridium difficile is a gram-positive obligate anaerobic spore-forming bacillus that can produce toxins in the intestine to cause disease in humans. Clostridium difficile infection can be asymptomatic carriers or mild diarrhea, and typical pseudomembranous enteritis, which can be life-threatening, has become the most common pathogen in healthcare-associated infectious diarrhea, and Clostridium difficile infection has gradually replaced methicillin-resistant Staphylococcus aureus in the primary position of healthcare-associated infection.

[0004] Fidaxomicin belongs to narrow-spectrum antibacterial drugs, mainly against gram-positive bacteria and anaerobes, and has very weak antibacterial activity against gram-negative bacteria. It mainly resists Clostridium difficile, and also has good antibacterial effect on Enterococcus and Staphylococcus. According to the data, fidaxomicin and its active metabolite OP-1118 both have activity, and the activity is similar to fidaxomicin.

[0005] Fidaxomicin is a macrolide antibiotic with a novel mechanism of action. It can specifically inhibit the RNA polymerase of Clostridium difficile, thereby preventing bacterial protein synthesis. This mechanism of action makes fidaxomicin different from other antibiotics, as it has less impact on the normal flora of the human body, reducing the risk of antibiotic-associated diarrhea.

[0006] The common adverse reactions of fidaxomicin include nausea, vomiting, headache, stomach pain and dysentery, etc.

[0007] Currently, there is no report of drug resistance of fidaxomicin in clinical trials and actual use, and there is no cross-resistance between fidaxomicin, metronidazole and other antibiotics. However, fidaxomicin has the phenomenon of natural mutation, although the probability of mutagenic mutation is very low, but fidaxomicin should also be further investigated and evaluated for the risk of mutation resistance in clinical use.

[0008] It is found in the current clinical use that the concentration of niddamycin in human plasma is low and has a large difference, and the active metabolite OP-1118 also has a similar situation, wherein the plasma of niddamycin is 0-6.8 ng·ml -1 ; the plasma concentration of active metabolite OP-1118 is 0-35 ng·ml -1 The reason for this is that the absorption of niddamycin and its active metabolite OP-1118 in the gastrointestinal tract is difficult, which is verified by the fact that less than 1% of niddamycin is excreted in urine, and most of the metabolites are in feces.

[0009] Current in vitro studies show that niddamycin is mainly hydrolyzed into active metabolite OP-1118 through O-isobutyryl at position 4, and the hydrolysis process of niddamycin and the formation of metabolites need to be completed in an acidic medium (such as gastric acid) and / or catalyzed by intestinal microsomal enzymes, rather than relying on the P450 enzyme system. Therefore, this is also the fundamental reason for the low and large difference in the in vivo absorption of niddamycin.

[0010] Therefore, there is an urgent need for a new pharmaceutical composition to solve the above technical problems. SUMMARY

[0011] In order to solve the above problems, the present application provides a bidirectional positioning release sustained-release pharmaceutical composition and a preparation method thereof, which solves the problem of low in vivo absorption of niddamycin and its active metabolite.

[0012] In one aspect, the present application discloses a bidirectional positioning release sustained-release pharmaceutical composition, which is a double-layer tablet, and the double-layer tablet comprises an upper layer tablet and a lower layer tablet. The upper layer tablet is a sustained-release intragastric positioning release preparation part, and contains 1 / 3 of the labeled amount of active ingredients; the components of the upper layer tablet are prepared by weight: active ingredients 5-10%, hydroxypropyl methylcellulose K4M 20-40%, carbomer 10-20%, pH adjuster 1-5%, PEG 5-10%, microcrystalline cellulose 10-20%, hydroxypropyl cellulose 1-5%, stabilizer 0.1-4%, and magnesium stearate 0.5-1%. The lower layer tablet is a rapid-release gastrointestinal release preparation part, and contains 2 / 3 of the labeled amount of active ingredients; the components of the lower layer tablet are prepared by weight: active ingredients 5-10%, siliconized microcrystalline cellulose 20-40%, disintegrant 1-5%, pH adjuster 1-5%, pH-dependent excipient 5-10%, hydroxypropyl cellulose 1-5%, stabilizer 0.1-4%, and magnesium stearate 0.5-1%.

[0013] Preferably, the active ingredient is niddamycin or a pharmaceutically acceptable salt thereof.

[0014] Preferably, the pH adjuster comprises one or more of sodium citrate, sodium citrate, and sodium bicarbonate. Preferably, the pH-dependent auxiliary material is one or more of hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose titanate, acrylic resin enteric, alginic acid.

[0015] Preferably, the disintegrating agent includes one or more of sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked polyvinyl pyrrolidone.

[0016] Preferably, the stabilizer includes one or more of disodium edetate, vitamin C or its sodium salt, butylated hydroxytoluene.

[0017] In another aspect, the present application also discloses a preparation method of the above pharmaceutical composition, which comprises: Step A, preparation of upper layer tablet granules, the steps comprising: ultrafine grinding the raw material of the nelfinavir; First, mix the nelfinavir and the stabilizer evenly, then sieve the hydroxypropyl methyl cellulose K4M, carbomer, and pH regulator through an 80-mesh sieve, and add them into a high-speed granulator and mix evenly; dissolve the hydroxypropyl cellulose (HPC) in an appropriate concentration of ethanol aqueous solution, add it into the high-speed granulator, and start the granulator to granulate; add PEG and microcrystalline cellulose, and add an appropriate amount of ethanol aqueous solution to granulate for the second time; transfer the above wet granular material to a drying device, dry until the moisture content is less than or equal to 2.5%, and then granulate to obtain the granules; mix the above obtained dry granules with magnesium stearate evenly and reserve them for use; Step B, preparation of lower layer tablet granules, the steps comprising: ultrafine grind the raw material of the nelfinavir and the pH-dependent auxiliary material, and control the particle size; first, mix the above material and the stabilizer evenly; then sieve the silicified microcrystalline cellulose, disintegrating agent, and pH regulator through an 80-mesh sieve, and add them into a high-speed granulator and mix evenly; dissolve the hydroxypropyl cellulose (HPC) in an appropriate concentration of ethanol aqueous solution, add it into the high-speed granulator, and start the granulator to granulate; transfer the above wet granular material to a drying device, dry until the moisture content is less than or equal to 2.5%, and then granulate to obtain the granules; mix the above obtained dry granules with magnesium stearate evenly and reserve them for use; use the double-layer tablet press to press the granules prepared in steps A and B to obtain the tablets.

[0018] Preferably, in steps A and B, the particle size of the ground material is controlled to be less than or equal to 10 μm.

[0019] Preferably, the drying equipment is a fluidized bed dryer or a fluidized bed dryer.

[0020] Preferably, the hardness of the pharmaceutical composition is 90-140 N. Compared with the prior art, the present application has the following advantages: 1) The present application adopts a new preparation technology and a new dosage form. The lower layer of the bilayer tablet can make the drug rapidly disintegrate in the stomach, and the disintegrated drug forms a granular dispersion, which can rapidly pass through the gastric emptying into the intestinal tract, thereby accelerating the absorption of the drug.

[0021] 2) The upper layer of the bilayer tablet prepared by the present application floats in the stomach after absorbing water, and the drug is slowly dissolved. The drug dissolved from the preparation can be metabolized into an active metabolite OP-1118 in the acidic environment (pH=2-4) in the stomach, and then the active metabolite is absorbed through the gastrointestinal tract. Part of the drug can also be uniformly and slowly absorbed into the intestinal tract, thereby improving the bioavailability. DETAILED DESCRIPTION

[0022] The technical solutions in the embodiments of the present application will be described below in a clear and complete manner. Obviously, the described embodiments are only a part of the embodiments of the present application, rather than all the embodiments.

[0023] Embodiment 1 The present embodiment discloses a technical solution for preparing 1000 pieces of bidirectional positioning release sustained-release pharmaceutical composition.

[0024] The prescription is shown in Table 1.

[0025] Table 1: Preparation method: Step A: preparation of upper layer tablet granules, the steps include: 1) The nelfinavir raw material is crushed by a super micro pulverizer, and the particle size is controlled to be D90≤10 μm; 2) First, nelfinavir, butylated hydroxytoluene and vitamin C sodium are uniformly mixed, then hydroxypropyl methyl cellulose (K4M), carbopol, sodium citrate are sieved through an 80 mesh sieve, and a high-speed granulator is used with a stirring knife of 200 rpm and a granulating knife of 1000 rpm, which is opened for 5-10 minutes; 3) Hydroxypropyl cellulose (HPC) is dissolved in 60% ethanol aqueous solution, and then added to the high-speed granulator, and the granulator is opened for 2-5 minutes with a stirring knife of 300 rpm and a granulating knife of 1200 rpm; 4) Then, PEG4000 and microcrystalline cellulose are added, and an appropriate amount of 60% ethanol aqueous solution is added, and the stirring knife is set to 300 rpm and the granulating knife is set to 1200 rpm, which is opened for 2-5 minutes for the second granulation; 5) The above wet granular material is transferred to a drying device for drying until the moisture content is less than or equal to 2.5%, and the granules are sized on a 24-30 mesh screen to obtain the granules; 6) The obtained granules are mixed with magnesium stearate and used as needed.

[0026] Step B: Preparation of lower-layer tablet granules, the steps comprising: 1) The filgrastim raw material and hydroxypropyl methylcellulose phthalate are ground together using a super micro grinder, and the particle size is controlled to be less than or equal to 10 μm; 2) The above material, butylated hydroxytoluene, and sodium ascorbate are mixed uniformly, and then the silicified microcrystalline cellulose, sodium citrate, and 80-mesh sieve are added to a high-speed granulator, the stirring knife is set to 200 rpm, the granulating knife is set to 1000 rpm, and the granulator is opened for 5-10 minutes; 3) Hydroxypropyl cellulose (HPC) is dissolved in an appropriate amount of 60% ethanol aqueous solution, and then added to a high-speed granulator, the granulator is opened for granulation, the stirring knife is set to 300 rpm, the granulating knife is set to 1200 rpm, and the granulator is opened for 2-5 minutes; 4) The above wet granular material is transferred to a drying device for drying until the moisture content is less than or equal to 3.0%, and the granules are sized to obtain the granules; 5) The obtained granules are mixed with sodium carboxymethyl starch and magnesium stearate and used as needed; 6) The granules prepared in steps A and B are compressed using a double-layer tablet press to obtain the tablets.

[0027] Example 2 The embodiment discloses a technical scheme for preparing 1000 tablets of bidirectional positioning release sustained-release pharmaceutical compositions.

[0028] The prescription is shown in Table 2.

[0029] Table 2: Preparation method: Step A: Preparation of upper-layer tablet granules, the steps comprising: 1) The filgrastim raw material is ground using a super micro grinder, and the particle size is controlled to be less than or equal to 10 μm; 2) The filgrastim, butylated hydroxytoluene, and sodium ascorbate are mixed uniformly, and then the hydroxypropyl methylcellulose (K4M), carbomer, and sodium citrate are sieved through an 80-mesh sieve and added to a high-speed granulator, the stirring knife is set to 200 rpm, the granulating knife is set to 1000 rpm, and the granulator is opened for 5-10 minutes; 3) Hydroxypropyl cellulose (HPC) is dissolved in 60% ethanol solution, and is added into the high-speed granulator. The granulator is started to granulate, with the stirring knife set at 300 rpm and the granulating knife set at 1200 rpm. The granulator is started for 2-5 minutes; 4) PEG6000 and microcrystalline cellulose are added, and an appropriate amount of 60% ethanol solution is added. The stirring knife is set at 300 rpm, the granulating knife is set at 1200 rpm, and the granulator is started for 2-5 minutes for the second granulation; 5) The wet granular material is transferred to a drying device for drying until the moisture content is less than or equal to 2.5%. The granules are sieved through a 24-30 mesh sieve to obtain the granules; 6) The obtained granules are mixed with magnesium stearate and are ready for use.

[0030] Step B: Preparation of lower layer granules, the steps comprising: 1) The filgrastim raw material and hypromellose phthalate are pulverized together by a super micro pulverizer, with the particle size controlled to be less than or equal to 10 μm; 2) The above-mentioned material, butylated hydroxytoluene, and sodium ascorbate are mixed uniformly. The siliconized microcrystalline cellulose and sodium citrate are sieved through an 80 mesh sieve and are added into the high-speed granulator. The stirring knife is set at 200 rpm, the granulating knife is set at 1000 rpm, and the granulator is started for 5-10 minutes for mixing; 3) Hydroxypropyl cellulose (HPC) is dissolved in an appropriate amount of 60% ethanol solution, which is added into the high-speed granulator. The granulator is started to granulate, with the stirring knife set at 300 rpm and the granulating knife set at 1200 rpm. The granulator is started for 2-5 minutes; 4) The wet granular material is transferred to a drying device for drying until the moisture content is less than or equal to 3.0%, and the granules are sieved through a 24-30 mesh sieve to obtain the granules; 5) The obtained granules are mixed with sodium carboxymethyl starch and magnesium stearate and are ready for use; 6) The granules prepared in steps A and B are compressed by a double-layer tablet press to obtain the tablets. 7) The tablets are ready for use. 8) The tablets are ready for use.

[0031] Example 3 The embodiment discloses a technical scheme for preparing 1000 tablets of bidirectional positioning release sustained-release pharmaceutical composition.

[0032] The prescription is shown in Table 3.

[0033] Table 3: Preparation method: Step A: Preparation of upper layer granules, comprising: 1) The filgrastim raw material is pulverized by a super micro pulverizer, with the particle size controlled to be less than or equal to 10 μm; 2) First, mix fenamidac, butylated hydroxytoluene, and sodium vitamin C evenly. Then, pass hydroxypropyl methylcellulose (K4M), carbomer, and sodium citrate through an 80-mesh sieve and add them to a high-speed granulator. Set the stirring blade to 200 rpm and the granulation blade to 1000 rpm, and run for 5-10 minutes. 3) Dissolve hydroxypropyl cellulose (HPC) in a 60% ethanol aqueous solution, add it to a high-speed granulator, turn on the granulator and set the stirring blade to 300 rpm and the granulating blade to 1200 rpm, and run for 2-5 minutes. 4) Add PEG4000, microcrystalline cellulose, and an appropriate amount of 60% ethanol aqueous solution. Set the stirring blade to 300 rpm and the granulation blade to 1200 rpm, and run for 2-5 minutes to perform the second granulation. 5) Transfer the above wet granular material to a drying device and dry it until the moisture content is ≤2.5%. Then, granulate it through a 24-30 mesh sieve to obtain the final product. 6) Mix the obtained dry granules with magnesium stearate evenly and set aside for later use.

[0034] Step B: Preparation of lower layer granules includes: 1) Fidamycin raw material and hydroxypropyl methylcellulose acetate succinate were pulverized together using an ultra-fine pulverizer, and the particle size was controlled to be D90≤10μm; 2) First, mix the above materials with butylated hydroxytoluene and sodium vitamin C evenly. Then, add the siliconized microcrystalline cellulose and sodium citrate through an 80-mesh sieve into a high-speed granulator. Set the stirring blade to 200 rpm and the granulation blade to 1000 rpm. Turn on the machine for 5-10 minutes and mix evenly. 3) Dissolve hydroxypropyl cellulose (HPC) in an appropriate amount of 60% ethanol aqueous solution, then add... In the high-speed granulator, turn on the granulator and set the stirring blade to 300 rpm and the granulating blade to 1200 rpm for 2-5 minutes. 4) Transfer the above wet granular material to a drying device and dry it until the moisture content is ≤3.0%. Whole grains are sufficient; 5) Mix the obtained dry granules with sodium carboxymethyl starch and magnesium stearate evenly and set aside for later use; 6) Compress the granules prepared in steps A and B into tablets using a double-layer tablet press to obtain the final product.

[0035] Example 4 This embodiment measures the release rate of the bidirectional targeted release sustained-release drug composition prepared in Examples 1-3 and a commercially available tablet (Fidamycin tablets from Optimer).

[0036] At the same time of doing the release determination, first of all, the in-vitro floating state of the tablets is investigated by the intuitive visual method. The floating-up time and the sustained floating time of the bidirectional positioning release sustained-release tablets of non-damycin in the medium are recorded.

[0037] 900ml of 0.1mol / L hydrochloric acid solution (0.8% sodium dodecyl sulfate is added) is used as the release medium, and under the condition of 37℃±0.5℃ and 75rpm, one piece of the bidirectional positioning release sustained-release tablets of non-damycin is put into each of 6 dissolution cups. At 0.25h, 0.5h, 0.75h, 1h, 1.5h, 2h, 4h, 8h, 10h and 12h, 10ml of the dissolution solution is taken, and at the same time, 0.1mol / L hydrochloric acid solution of the same temperature and volume is added. The taken solution is filtered, and the content of the continued filtrate is detected. The specific results are shown in the following Table 4.

[0038] Table 4: From the above Table 4, it can be seen that compared with the commercial tablets, the release speed of the bidirectional positioning release sustained-release pharmaceutical composition prepared in the examples 1-3 is more stable, the fluctuation is smaller, and the release degree of the commercial tablets is obviously slow, which is not conducive to the absorption of the drug.

[0039] Example 5 In this example, the in-vivo pharmacokinetic experiment of the bidirectional positioning release sustained-release pharmaceutical composition prepared in the example 1 and the commercial tablets (non-damycin tablets of Optimer Company) is carried out.

[0040] 12 beagles (the weight range is 8Kg-10Kg) are taken, and are randomly divided into 2 groups, 6 in each group, and are respectively given the whole piece of the bidirectional positioning release sustained-release pharmaceutical composition prepared in the example 1 and the commercial tablets of the dissolution tablets each 1 piece, and 0.50mL of the solution is taken from the posterior radial vein after 15min, 30min, 45min, 1h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 18h and 24h of administration, acetonitrile is added, and is vortexed and shaken for 1min, centrifuged, and the supernatant 20μl is taken for detection of the content, and the pharmacokinetic parameters of each preparation in-vivo are shown in the following Table 5.

[0041] Table 5: The results of the above table show that the Tmax and AUC of the example 1 and the commercial tablets have significant differences.

[0042] Therefore, compared with the commercial preparation, the bidirectional positioning release sustained-release pharmaceutical composition prepared according to the example 1 has the further prolonged peak time, and the AUC is much larger than that of the commercial preparation, and has significant differences, and it can be considered that the present application has a significant improvement of the curative effect.

[0043] The above merely describes some embodiments of the present application, and it should be pointed out that, for those skilled in the art, other variations and improvements can be made without departing from the inventive concept of the present application, and these all belong to the protection scope of the present application.

Claims

1. A bidirectional positioning release extended release pharmaceutical composition, characterized in that, The pharmaceutical composition is a double-layer tablet, the double-layer tablet comprising an upper layer tablet and a lower layer tablet; the upper layer tablet is a sustained-release intragastric positioning release preparation part containing 1 / 3 of the labeled amount of active ingredient; the components of the upper layer tablet are prepared by weight: active ingredient 5-10%, hydroxypropyl methylcellulose K4M 20-40%, carbomer 10-20%, pH adjuster 1-5%, PEG 5-10%, microcrystalline cellulose 10-20%, hydroxypropyl cellulose 1-5%, stabilizer 0.1-4%, magnesium stearate 0.5-1%; the lower layer tablet is a rapid-release gastrointestinal release preparation part containing 2 / 3 of the labeled amount of active ingredient; the components of the lower layer tablet are prepared by weight: active ingredient 5-10%, siliconized microcrystalline cellulose 20-40%, disintegrant 1-5%, pH adjuster 1-5%, pH-dependent excipient 5-10%, hydroxypropyl cellulose 1-5%, stabilizer 0.1-4%, magnesium stearate 0.5-1%.

2. The pharmaceutical composition according to claim 1, wherein The active ingredient is non-darunavir or a pharmaceutically acceptable salt thereof.

3. The pharmaceutical composition according to claim 2, wherein The pH adjuster comprises one or more of sodium citrate, sodium citrate, sodium bicarbonate.

4. The pharmaceutical composition according to claim 3, wherein The pH-dependent excipient is one or more of hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose titanate, acrylic acid resin enteric, alginic acid.

5. The pharmaceutical composition according to claim 4, wherein The disintegrant comprises one or more of sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked polyvinyl pyrrolidone.

6. The pharmaceutical composition according to claim 5, wherein The stabilizer comprises one or more of disodium edetate, vitamin C or its sodium salt, butylated hydroxytoluene.

7. Process for the preparation of a pharmaceutical composition according to any one of claims 1 to 6, characterized in that, The preparation method comprises: Step A, upper layer tablet granule preparation, the steps comprising: Ultrafine grinding of non-darunavir raw material, controlling particle size; First, mix non-darunavir and stabilizer evenly, then pass hydroxypropyl methylcellulose K4M, carbomer, and pH adjuster through an 80-mesh sieve, and add them to a high-speed granulator, mix evenly; Dissolve hydroxypropyl cellulose (HPC) in an appropriate concentration of ethanol aqueous solution, add it to the high-speed granulator, and start the granulator; Add PEG and microcrystalline cellulose, and add an appropriate amount of ethanol aqueous solution for secondary granulation; Transfer the above wet granular material to a drying device, dry until the moisture content is ≤2.5%, and then size the granules; Mix the above obtained dry granules with magnesium stearate evenly and reserve for use; Step B, lower layer tablet granule preparation, the steps comprising: Ultrafine grinding of non-darunavir raw material and pH-dependent excipient, controlling particle size; First, mix the above materials and stabilizer evenly; then pass siliconized microcrystalline cellulose, disintegrant, and pH adjuster through an 80-mesh sieve, and add them to a high-speed granulator, mix evenly; Dissolve hydroxypropyl cellulose (HPC) in an appropriate concentration of ethanol aqueous solution, add it to the high-speed granulator, and start the granulator; Transfer the above wet granular material to a drying device, dry until the moisture content is ≤2.5%, and then size the granules; Mix the above obtained dry granules with magnesium stearate evenly and reserve for use; Use a double-layer tablet press to press the granules prepared in steps A and B, and obtain the tablet.

8. The preparation method according to claim 7, characterized in that, In steps A and B, the particle size of the ground material is controlled to be D90≤10 μm.

9. The preparation method according to claim 7, characterized in that, The drying equipment is fluidized bed drying or boiling drying machine drying.

10. The preparation method according to claim 7, characterized in that, The hardness of the pharmaceutical composition is 90-140 N.

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